Levodopa prodrugs, and compositions and uses thereof

ABSTRACT

Prodrugs of levodopa, methods of making prodrugs of levodopa, methods of using prodrugs of levodopa, and compositions of prodrugs of levodopa are disclosed.

This application claims benefit of U.S. Provisional Application No.60/577,087 filed Jun. 4, 2004, which is incorporated by reference hereinin its entirety.

Embodiments of the present invention are directed to prodrugs oflevodopa, methods of making prodrugs of levodopa, methods of usingprodrugs of levodopa, and compositions of prodrugs of levodopa.

Parkinson's disease is a disabling, progressive illness that affects onein 1,000 people and generally occurs in people over the age of 50 years.Patients with Parkinson's disease have a deficiency of theneurotransmitter dopamine in the brain as a result of the nigrostriatalpathway disruption caused by degeneration of the substantia nigra.Levodopa (L-dopa or L-3,4-dihydroxyphenylalanine), an immediateprecursor of dopamine, is the most commonly prescribed drug fortreatment of this disease.

Following oral administration, levodopa is rapidly absorbed via an aminoacid transporter present in the upper small intestine. Due to the narrowdistribution of this transporter system, the window available forlevodopa absorption is limited and the extent of absorption can bedependent on the rate at which the drug passes through the uppergastrointestinal tract. Approximately 35% of the administered dosereaches the systemic circulation as intact levodopa after oraladministration in patients (Sasahara, 1980, J. Pharm. Sci., 69, 261).The absolute bioavailability of levodopa is dose-dependent, due tosaturation of the active transport pathway. Plasma levels of levodopamust be carefully titrated for each patient to achieve the optimaltherapeutic activity. If the concentration of levodopa is too low inplasma (and consequently in the brain) the patient can experience areturn of the symptoms of Parkinson's disease (rigidity, tremor,bradykinesia). On the other hand, motor fluctuation can become asignificant side effect if plasma drug levels are too high. Uncontrolledfluctuations in plasma levodopa levels can greatly contribute to theincidence of “on-off” fluctuations (dyskinesias). The most effectivecontrol of Parkinsonism is observed when plasma levels of levodopa aremaintained in a narrow range, for example, by continuous intraduodenalinfusion.

Once absorbed, levodopa is rapidly converted to dopamine by L-aromaticamino acid decarboxylase (AADC) in the peripheral tissues (e.g.,intestines and liver). It has been known that intestinal metabolism oflevodopa is the major source of first pass loss of the drug. Inpatients, only 1% of the administered dose reaches the central nervoussystem intact, following transport across the blood-brain barrier by theneutral amino acid transporter. For this reason, levodopa is normallyco-administered with a drug designed to inhibit its peripheraldecarboxylation such as carbidopa or benserazide. When administered withcarbidopa, the plasma intact levodopa amount increases and thus morelevodopa becomes available to be transported into the central nervoussystem where it is converted to dopamine. Carbidopa and benserasidethemselves do not cross the blood-brain barrier to a significant extent,and therefore do not inhibit the required conversion of levodopa todopamine in the brain.

The oral bioavailability of levodopa from conventional formulations oflevodopa/carbidopa (e.g., Sinemet®) is 84-99% (Physician's DeskReference). The half-life of levodopa in the plasma of patients is about50 min when administered alone, or 1 to 2 hours when given withcarbidopa. For this reason, the drug must be administered three or moretimes per day.

A formulation of levodopa/carbidopa (Sinemet® CR) intended to provide acontrolled release of both drugs is commercially available. Sinemet® CRis designed for release of both levodopa and carbidopa over a 4-6 hourperiod. However, absorption of levodopa is limited to the smallintestine and the resulting bioavailability of levodopa from Sinemet® CRis reduced relative to the immediate release product. In most cases,Sinemet® CR must also be given more than twice per day to achieve atherapeutic level of levodopa. Delayed and extended release formulationsthat release drug over periods of about 10-24 hours, and hence releasemuch of the drug loading in the large intestine, have not been effectivefor delivering levodopa since levodopa is poorly absorbed from the largeintestine. A simple enteric-coated formulation of levodopa led toincreased gastrointestinal side effects (nausea) but did not improveabsorption. A sustained release formulation of levodopa/carbidopa hasbeen described that employs a swellable matrix (Geomatrix) deliverysystem to retain the drug in the stomach (Genta Jago product licensinginformation, June 1997). However, this formulation was designed to bebioequivalent to the commercially available Sinemet® CR formulation andtherefore does not provide the desired goal of a once or twice per daydosing regimen.

The use of simple ester prodrugs of levodopa to improve thepharmacokinetics of the drug has been proposed (U.S. Pat. Nos.5,017,607; 4,826,875; 4,873,263; 4,771,073; 4,663,349; 4,311,706;Japanese Patent No. JP58024547; Juncos et al., 1987, Neurology, 37:1242;and Cooper et al., 1987, J. Pharm. Pharmacol., 39:627-635). An oralformulation of levodopa methyl ester (Levomet®, CHF 1301) has beendescribed (Chiesi Pharmaceuticals). The ethyl ester of levodopa(TV-1203) is under clinical investigation as a potential therapy forParkinsonism when co-administered with carbidopa (U.S. Pat. No.5,607,969). A sustained cellulose formulation of levodopa ethyl ester ina mixture of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, anda carboxyvinyl polymer has been described (U.S. Pat. No. 5,840,756).However, oral administration of this formulation to healthy adultspretreated with carbidopa produced a plasma levodopa terminal half-lifeof only 2 hr, comparable to that of Sinemet® CR.

A pivaloyl ester of levodopa (NB-355) has been described (EuropeanPatent No. 0 309 827). Following oral administration of NB-355, no rapidincrease or elimination of levodopa was observed and duration time wasprolonged, while levels of levodopa were low. The potential for usingester prodrugs of levodopa to enhance rectal absorption of the drug hasbeen described (U.S. Pat. Nos. 4,663,349; 4,771,073; and 4,873,263).Notably, the absorption of simple alkyl esters of levodopa has beenshown to be greater following rectal absorption than following oraldosing (Fix, et al., Pharm. Res., 1989, 6:501-5; Fix, et al., Pharm.Res., 1990, 4:384-7). This effect is attributed to the decreasedabundance of esterases in the large intestine relative to the smallintestine. Therefore, selective delivery of a prodrug of levodopa to thelarge intestine in a sustained release formulation might be expected toprovide a greater oral bioavailability and a prolonged exposure to thedrug.

A series of glycolic acid ester containing prodrugs of levodopa has beendescribed (Wermuth, U.S. Pat. No. 4,134,991). Lipid conjugates oflevodopa to facilitate the entry of drug into cells and tissues havealso been described (Yatvin, U.S. Pat. No. 5,827,819).

The half-life of levodopa is prolonged and its bioavailability increasedby the co-administration of carbidopa. Both drugs have relatively shorthalf-lives of less than about 2 hours. Any method of sustained deliveryof levodopa to the systemic circulation would therefore require asufficient level of carbidopa to continuously inhibit peripheraldecarboxylation of levodopa. In order to avoid the need for frequent(more than twice per day) dosing of levodopa and carbidopa, it isdesirable to deliver both levodopa and carbidopa (or prodrug thereof) ina sustained manner. It has been proposed that rectal co-administrationof an AADC inhibitor such as carbidopa with an ester prodrug of levodopawould be possible as a means to decrease metabolic clearance of levodopa(U.S. Pat. Nos. 4,663,349; 4,771,073; and 4,873,263). However, studiesin rats have since indicated that absorption of carbidopa followingrectal administration is poor (Leppert et al., 1988, Pharm. Res.,5:587-591).

Thus, the development of levodopa prodrugs that can be efficientlyabsorbed throughout the gastrointestinal tract, including the colon, andreduce first-pass metabolism of levodopa, is highly desirable.

Certain embodiments of the present invention are related to prodrugs oflevodopa, which are capable of undergoing absorption across theintestinal epithelium via active and/or passive transport.

Certain embodiments of the present invention are related to prodrugs oflevodopa which are capable of undergoing absorption across theintestinal epithelium via active transport mechanisms, and moreparticularly to levodopa prodrugs that are substrates for organic cationtransporters expressed throughout the gastrointestinal tract.

The human gastrointestinal tract includes the small intestine and thelarge intestine. The human small intestine is a convoluted tube abouttwenty feet in length between the stomach and large intestine. The smallintestine is subdivided into the duodenum, the jejunum, and the ileum.The large intestine is about 5 feet in length and runs from the ileum tothe anus. The large intestine is divided into the caecum, colon, and therectum. The colon is divided into four parts including the ascending,traverse, descending, and the sigmoid flexure. In general, an orallyingested compound resides about 1 to 6 hours in the stomach, about 2 to7 hours in the small intestine, and about 8 to 18 hours in the colon.Thus, the greatest period of time for sustained release of a compoundoccurs when the compound is passing through the colon.

Certain active transporter proteins are known to be expressed throughoutthe gastrointestinal tract. An active transporter refers to amembrane-bound protein that recognizes a substrate and affects the entryof the substrate into, or exit from a cell by carrier-mediated transportor receptor-mediated transport. Active transport includes movement ofmolecules across cellular membranes that is directly or indirectlydependent on an energy mediated process, such as for example is drivenby ATP hydrolysis or an ion gradient, that occurs by facilitateddiffusion mediated by interaction with specific transporter proteins,and that occurs through a modulated solute channel. For example, organiccation transporters such as OCTN1 and OCTN2 are expressed in theepithelial cells lining a human colon as well as in the small intestine.

Thus, levodopa prodrugs that act as substrates for one or more organiccation transporter(s) can exhibit increased active transporter-mediatedabsorption during the extended period of time that the compound passesthrough the gastrointestinal tract. Increased absorption and inparticular colonic absorption of levodopa prodrug can result in theincreased systemic bioavailability of the compound over an extendedperiod of time. Systemic bioavailability refers to the rate and extentof systemic exposure to a drug or an active metabolite thereof asreflected in the integrated systemic blood concentration over a periodof time, also referred to as “area under the curve.”

In certain embodiments, levodopa prodrugs are capable of absorption overa significant length of the gastrointestinal tract, including the largeintestine, and in particular the colon. Such prodrugs can beincorporated into conventional sustained release formulations includingosmotic delivery devices to provide sustained systemic exposure tolevodopa upon oral administration to a patient. Many of such prodrugscan be coadministered with a decarboxylase inhibitor such as carbidopaor benserazide, or a prodrug of thereof, and in some embodiments alsoformulated as sustained release compositions, with thecarbidopa/levodopa prodrug compositions or benserazide/levodopa prodrugcompositions together providing prolonged exposure to levodopa at levelsnecessary to affect sustained anti-Parkinson's therapy. Certainembodiments include carbidopa prodrugs that can block first-passlevodopa decarboxylation within the intestinal enterocytes either as theintact carbidopa prodrug, or through generation of carbidopa fromcarbidopa prodrug cleavage within the enterocytes and which can becleaved to provide carbidopa in the systemic circulation. Decarboxylaseinhibitor/levodopa prodrug or decarboxylase inhibitor prodrug/levodopaprodrug sustained release compositions can also be administered togetherwith inhibitors of catechol O-methyltransferase (COMT) such asentacapone or tolcapone, to further block peripheral clearance oflevodopa.

Among levodopa prodrugs contemplated by certain embodiments are prodrugsin which the carboxyl moiety of levodopa is masked to form a carboxylester, which can be cleaved in vivo to release the parent drug (e.g.,levodopa). Optionally, the catechol moieties of levodopa canadditionally be masked with promoieties, these promoieties being cleavedeither before or after cleavage of the carboxyl ester promoiety.

Suitable catechol protecting moieties in the aforementioned prodrugs canbe elaborated by functionalizing one or more of the phenolic hydroxygroups via acylation or other appropriate methods. The correspondingesters, carbonates, and (hemi)acetals/(hemi)ketals can be cleaved invivo to regenerate the catechol moieties of the parent drug.

Certain embodiments of the present invention provide at least onelevodopa prodrug of Formula (I)

a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein

Q is selected from —X—CO—, and —CO—X—;

X is selected from —O—, and —NR⁶—;

n is an integer from 2 to 4;

each R¹ and R² is independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl;

R³ and R⁴ are independently selected from hydrogen, C(O)OR⁷, —C(O)R⁷,and —(CR⁸R⁹)OC(O)R¹⁰;

R⁵ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, heteroalkyl, substituted heteroalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and when Qis —X—CO, R⁵ is further selected from alkoxy, substituted alkoxy,cycloalkoxy, and substituted cycloalkoxy;

R⁶ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, and substituted arylalkyl;

R⁷ is selected from alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

R⁸ and R⁹ are independently selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,and substituted heteroarylalkyl, or optionally, R⁸ and R⁹ together withthe carbon atom to which R⁸ and R⁹ are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring; and

R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, heteroalkyl, substituted heteroalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

with the proviso that the compound of Formula (I) is not derived from1,3-dihexadecanoylpropane-1,2,3-triol.

Certain embodiments of the present invention provide compositionscomprising at least one levodopa prodrug. In certain embodiments, thecompositions comprise at least one levodopa prodrug, or an enantiomerand stereoisomer of any of the foregoing, or a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing and a pharmaceutically acceptable diluent, carrier, excipientand/or adjuvant of any of the foregoing. The choice of diluent, carrier,excipient and/or adjuvant can depend upon, among other factors, thedesired mode of administration.

Certain embodiments of the present invention provide methods of treatingParkinson's disease. The methods comprise co-administering to a patientin need of such treatment a therapeutically effective amount of at leastone of the following: (i) at least one levodopa prodrug; (ii) at leastone levodopa prodrug and at least one decarboxylase inhibitor; (iii) atleast one levodopa prodrug and at least one decarboxylase inhibitorprodrug; (iv) a stereoisomer or an enantiomer of any of the foregoing;and (v) a pharmaceutically acceptable salt thereof, a hydrate thereof ora solvate of any of the foregoing. In certain embodiments, thecomposition is administered to a patient using a sustained-releasedosage form.

In certain embodiments, the at least one levodopa prodrug can bereleased from the dosage form, e.g., an orally administered dosage form,over a sufficient period of time to provide prolonged therapeuticconcentrations of levodopa in the blood of a patient enablingadministration of the dosage form on only a once or twice per day basis.In certain embodiments, the at least one levodopa prodrug can maintain atherapeutic or prophylactic blood concentration of levodopa or levodopaprodrug in the systemic circulation of a patient following oraladministration of a levodopa prodrug over a period of at least 4 hours,in certain embodiments, over a period of at least 8 hours, and incertain embodiments, over a period of at least 12 hours. Similarly, adecarboxylase inhibitor (e.g., carbidopa, benserazide or prodrugthereof), when dosed with a levodopa prodrug, can be released from thedosage form or device immediately after the dosage form is administered,over a period of hours up to, for example, 16 hours after administrationof the dosage form with greater than 75% of the decarboxylase inhibitorreleased, or coextensively released with the release of the levodopaprodrug.

The oral sustained release dosage forms used with certain embodimentscan take any form as long as the release characteristics andpharmacokinetic profiles above are satisfied. For example, the dosageform can be in the form of an osmotic dosage form, a prodrug-releasingpolymer, prodrug-releasing tiny timed-release pills, prodrug-releasinglipids, prodrug-releasing waxes and/or prodrug-releasing beads.

Certain embodiments of the present invention provide compositions fortreating Parkinson's disease in a patient in need of such treatment. Thecompositions comprise a therapeutically effective amount of at least oneof the following: (i) levodopa prodrug; (ii) levodopa prodrug anddecarboxylase inhibitor; (iii) levodopa prodrug and decarboxylaseinhibitor prodrug; (iv) a stereoisomer or an enantiomer of any of theforegoing; and (v) a pharmaceutically acceptable salt thereof, a hydratethereof or a solvate of any of the foregoing. In certain embodiments,the composition further comprises a sustained-release dosage form.

Certain embodiments of the present invention methods for making levodopaprodrugs, compositions comprising at least one levodopa prodrug, methodsof using levodopa prodrugs, and methods of using compositions comprisingat least one levodopa prodrug for treating Parkinson's disease.

SPECIFIC EMBODIMENTS Definitions

Unless otherwise indicated, all numbers expressing quantities ofingredients, reaction conditions, and so forth used in the specificationand claims are to be understood as being modified in all instances bythe term “about.” Accordingly, unless indicated to the contrary, thenumerical parameters set forth in the following specification andattached claims are approximations that may vary depending upon theproperties sought to be obtained. At the very least, and not as anattempt to limit the application of the doctrine of equivalents to thescope of the claims, each numerical parameter should at least beconstrued in light of the number of reported significant digits and byapplying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the embodiments are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical values, however, inherently contain certainerrors necessarily resulting form the standard deviation found in theirrespective testing measurements.

To the extent the definitions of terms in the publications, patents, andpatent applications incorporated herein by reference are not the same asthe definitions set forth in this specification, the definitions in thisspecification control for the entire specification, including theclaims. Any other definitions in the publications, patents, and patentapplications incorporated herein by reference that are not explicitlyprovided in this specification apply only to the embodiments discussedin the publications, patents, and patent applications incorporatedherein by reference.

“Compounds” refers to compounds encompassed by generic formulaedisclosed herein, any subgenus of those generic formulae, and anyspecific compounds within those generic or subgeneric formulae. Thecompounds can be a specific specie, a subgenus or larger genusidentified either by their chemical structure and/or chemical name.Further, compounds also include substitutions or modifications of any ofsuch species, subgenuses or genuses, which are set forth herein. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound. Thecompounds can contain one or more chiral centers and/or double bonds andtherefore, can exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers or diastereomers. Accordingly,the chemical structures within the scope of the specification encompassall possible enantiomers and stereoisomers of the illustrated compoundsincluding the stereoisomerically pure form (e.g., geometrically pure,enantiomerically pure or diastereomerically pure) and enantiomeric andstereoisomeric mixtures. Further, when partial structures of thecompounds are illustrated, asterisks indicate the point of attachment ofthe partial structure to the rest of the molecule. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan.

“Alkyl” refers to a saturated or unsaturated, branched, straight-chainor cyclic monovalent hydrocarbon group derived by the removal of onehydrogen atom from a single carbon atom of a parent alkane, alkene oralkyne. Typical alkyl groups include, but are not limited to, methyl;ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl,propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl,prop-1-yn-1-yl, prop-2-yn-1-yl; butyls such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. In certain embodiments, an alkylgroup comprises from 1 to 20 carbon atoms.

“Alkanyl” refers to a saturated branched, straight-chain or cyclic alkylgroup derived by the removal of one hydrogen atom from a single carbonatom of a parent alkane. Typical alkanyl groups include, but are notlimited to, methanyl; ethanyl; propanyls such as propan-1-yl,propan-2-yl(isopropyl), cyclopropan-1-yl; butanyls such as butan-1-yl,butan-2-yl(sec-butyl), 2-methyl-propan-1-yl(isobutyl),2-methyl-propan-2-yl(t-butyl), cyclobutan-1-yl; and the like.

“Alkenyl” refers to an unsaturated branched, straight-chain or cyclicalkyl group having at least one carbon-carbon double bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkene. The group can be in either the cis or trans conformation aboutthe double bond(s). Typical alkenyl groups include, but are not limitedto, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl,prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl;cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl,2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl,buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl,cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl; and the like.

“Alkynyl” refers to an unsaturated branched, straight-chain or cyclicalkyl group having at least one carbon-carbon triple bond derived by theremoval of one hydrogen atom from a single carbon atom of a parentalkyne. Typical alkynyl groups include, but are not limited to, ethynyl;propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such asbut-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.

“Alkylene” refers to a saturated or unsaturated, branched,straight-chain or cyclic divalent hydrocarbon group derived by theremoval of two hydrogen atoms from a parent alkane, alkene or alkyne.Typical alkylene groups include, but are not limited to methylene,ethylene, propylene, butylenes, and the like.

“Acyl” refers to a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to, formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

“Alkoxy” refers to a radical —OR where R represents an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, andthe like.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexylene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene, and the like. In certainembodiments, an aryl group comprises from 6 to 20 carbon atoms.

“Arylene” refers to a divalent aromatic hydrocarbon group derived byremoval of two hydrogen atoms from a parent aromatic ring system.

“Arylalkyl” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl group. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl,2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and thelike. Where specific alkyl moieties are intended, the nomenclaturearylalkanyl, arylalkenyl, and/or arylalkynyl is used. In certainembodiments, an arylalkyl group is (C₆-C₃₀) arylalkyl, e.g., thealkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C₁-C₁₀)and the aryl moiety is (C₅-C₂₀).

“Arylalkylene” refers to a divalent acyclic alkyl group in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom is replaced with an aryl group.

“Arylalkyloxy” refers to an —O-arylalkyl group where arylalkyl is asdefined herein.

“Cyano” refers to the radical —CN.

“Cycloalkyl” refers to a saturated or unsaturated cyclic alkyl group.Where a specific level of saturation is intended, the nomenclature“cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groupsinclude, but are not limited to, groups derived from cyclopropane,cyclobutane, cyclopentane, cyclohexane, and the like. In a certainembodiment, the cycloalkyl group is (C₃-C₁₀) cycloalkyl, or in certainembodiments (C₃-C₆) cycloalkyl.

“Cycloheteroalkyl” refers to a saturated or unsaturated cyclic alkylgroup in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atom(s) include, but are notlimited to, N, P, O, S, and Si. Where a specific level of saturation isintended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl”is used. Typical cycloheteroalkyl groups include, but are not limitedto, groups derived from epoxides, imidazolidine, morpholine, piperazine,piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

“Compound of Formula (I) derived from1,3-dihexadecanoylpropane-1,2,3-triol” refers to a moiety of structuralformula:

“Halo” refers to fluoro, chloro, bromo, or iodo.

“Heteroalkyloxy” refers to an —O-heteroalkyl group where heteroalkyl isas defined herein.

“Heteroalkyl, Heteroalkanyl Heteroalkenyl Heteroalkynyl” refer to alkyl,alkanyl, alkenyl, and alkynyl groups, respectively, in which one or moreof the carbon atoms (and any associated hydrogen atoms) are eachindependently replaced with the same or different heteroatomic groups.Typical heteroatomic groups include, but are not limited to, —O—, —S—,—O—O—, —S—S—, —O—S—, —NR′—, ═N—N═, —N═N—, —N═N—NR′—, —PH—, —P(O)₂—,OP(O)₂—, —S(O)—, —S(O)₂—, —SnH₂—, and the like, wherein R′ is hydrogen,alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl orsubstituted aryl.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. In certain embodiments, theheteroaryl group is between 5-20 membered heteroaryl, and in otherembodiments is between 5-10 membered heteroaryl. In certain embodiments,heteroaryl groups are those derived from thiophene, pyrrole,benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole,oxazole, and pyrazine.

“Heteroaryloxycarbonyl” refers to a radical —C(O)—OR where R isheteroaryl as defined herein.

“Heteroarylalkyl” refers to an acyclic alkyl group in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heteroaryl group. Where specific alkylmoieties are intended, the nomenclature heteroarylalkanyl,heteroarylalkenyl, and/or heteroarylalkynyl is used. In certainembodiments, the heteroarylalkyl group is a 6-30 memberedheteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of theheteroarylalkyl is 1-10 membered and the heteroaryl moiety is a5-20-membered heteroaryl.

“Leaving group” has the meaning conventionally associated with it insynthetic organic chemistry, i.e., an atom or a group capable of beingdisplaced by a nucleophile and includes halo (such as chloro, bromo, andiodo), acyloxy (e.g., acetoxy, and benzoyloxy), mesyloxy, tosyloxy,trifluoromethanesulfonyloxy, aryloxy (e.g., 2,4-dinitrophenoxy),methoxy, N,O-dimethylhydroxylamino, and the like.

“Pharmaceutically acceptable” refers to approved or approvable by aregulatory agency of the Federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized pharmacopeia for use inanimals, and more particularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound thatis pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine,dicyclohexylamine, and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound is administered.

“Extended release” refers to dosage forms that provide for the delayed,slowed over a period of time, continuous, discontinuous, or sustainedrelease of a compound or composition.

“Patient” includes mammals and humans. The terms “human” and “patient”are used interchangeably herein.

“Prodrug” refers to a derivative of a drug molecule that requires one ormore transformations, e.g., metabolism of the prodrug within thepatient's body to cause the active drug to be formed. Prodrugs can be(though not necessarily) pharmacologically inactive until converted tothe parent drug.

“Promoiety” refers to a group that is covalently attached to an activemolecule that is potentially cleavable in vivo by enzymatic ornon-enzymatic means. A promoiety can be, for example, a protecting groupused to mask a functional group, a group that acts as a substrate forone or more active or passive transport mechanisms, or a group that actsto impart or enhance a certain property to the molecule, such as, forexample, solubility.

“Protecting group” refers to a grouping of atoms that when attached to areactive group in a molecule masks, reduces or prevents that reactivity.Examples of protecting groups can be found in Green et al., “ProtectiveGroups in Organic Chemistry,” (Wiley, 2^(nd) ed. 1991) and Harrison etal., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wileyand Sons, 1971-1996). Representative amino protecting groups include,but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl,benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl(“TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substitutedtrityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”), and the like. Representative hydroxyprotecting groups include, but are not limited to, those where thehydroxy group is either acylated or alkylated such as benzyl, and tritylethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilylethers, and allyl ethers.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, —X, —R³³, —O⁻, ═O,—OR³³, —SR³³, —S⁻, ═S, —NR³³R³⁴, ═NR³³, —CX₃, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R³³, —OS(O₂)O⁻,—OS(O)₂R³³, —P(O)(O⁻)₂, —P(O)(OR³³)(O⁻), —OP(O)(OR³³)(OR³⁴), —C(O)R³³,—C(S)R³³, —C(O)OR³³, —C(O)NR³³R³⁴, C(O)O⁻, —C(S)OR³³, —NR³⁵C(O)NR³³R³⁴,—NR³⁵C(S)NR³³R³⁴, —NR³⁵C(NR³³)NR³³R³⁴ and —C(NR³³)NR³³R³⁴, where each Xis independently a halogen; each R³³ and R³⁴ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NR³⁵R³⁶, —C(O)R³⁵ or —S(O)₂R³⁵ or optionally R³³ andR³⁴ together with the atom to which R³³ and R³⁴ are attached form acycloheteroalkyl or substituted cycloheteroalkyl ring; and R³⁵ and R³⁶are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl. In certain embodiments,a substituent group is selected from halo, —CN, —NO₂, —OH, C₁₋₆ alkyl,and C₁₋₆ alkoxy. In certain embodiments, a substituent group is selectedfrom halo, —OH, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

“Treating” or “treatment” of any disease or disorder refers to arrestingor ameliorating a disease or disorder, reducing the risk of acquiring adisease or disorder, reducing the development of a disease or disorderor at least one of the clinical symptoms of the disease or disorder, orreducing the risk of developing a disease or disorder or at least one ofthe clinical symptoms of a disease or disorder. “Treating” or“treatment” also refers to inhibiting the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both,and inhibiting at least one physical parameter which may not bediscernible to the patient. Further, “treating” or “treatment” refers todelaying the onset of the disease or disorder or at least symptomsthereof in a patient which may be exposed to or predisposed to a diseaseor disorder even though that patient does not yet experience or displaysymptoms of the disease or disorder.

“Therapeutically effective amount” refers to the amount of a compoundthat, when administered to a patient for treating a disease or disorder,is sufficient to affect such treatment for the disease or disorder. The“therapeutically effective amount” will vary depending on the compound,the disease or disorder and its severity and the age and weight of thepatient to be treated.

“Cleave” refers to breakage of chemical bonds and is not limited tochemical or enzymatic reactions or mechanisms unless clearly indicatedby the context.

Reference will now be made in detail to certain embodiments.

Compounds

Compounds include levodopa prodrugs to which promoieties have beenattached. In certain embodiments, compounds include levodopa derivativesof Formula (I):

a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein

Q is selected from —X—CO—, and —CO—X—;

X is selected from —O—, and —NR⁶—;

n is an integer from 2 to 4;

each R¹ and R² is independently selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, halo, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, andsubstituted heteroarylalkyl;

R³ and R⁴ are independently selected from hydrogen, —C(O)OR⁷, —C(O)R⁷,and —(CR⁸R⁹)OC(O)R¹⁰;

R⁵ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, heteroalkyl, substituted heteroalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and when Qis —X—CO, R⁵ is further selected from alkoxy, substituted alkoxy,cycloalkoxy, and substituted cycloalkoxy;

R⁶ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, and substituted arylalkyl;

R⁷ is selected from alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl;

R⁸ and R⁹ are independently selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl,and substituted heteroarylalkyl, or optionally, R⁸ and R⁹ together withthe carbon atom to which R¹⁶ and R¹⁷ are attached form a cycloalkyl,substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkylring; and

R¹⁰ is selected from hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, heteroalkyl, substituted heteroalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

with the proviso that the compound of Formula (I) is not derived from1,3-dihexadecanoylpropane-1,2,3-triol.

In certain embodiments of a compound of Formula I, Q is —X—CO—. Incertain embodiments of a compound of Formula I, wherein Q is —X—CO—, Xis O. In certain embodiments of a compound of Formula I, wherein Q is—X—CO—, X is —NR⁶—.

In certain embodiments of a compound of Formula I, Q is —CO—X—. Incertain embodiments of a compound of Formula I, wherein Q is —CO—X, X isO. In certain embodiments of a compound of Formula I, wherein Q is—CO—X, X is —NR⁶—.

In certain embodiments of a compound of Formula I, each R¹ and R² isindependently selected from hydrogen, —OH, C₁₋₆ alkyl, and substitutedC₁₋₆ alkyl.

In certain embodiments of a compound of Formula I, each R¹ and R² isindependently selected from hydrogen, —OH, C₁₋₃ alkyl, and substitutedC₁₋₃ alkyl.

In certain embodiments of a compound of Formula I, R⁵ is selected fromalkanyl, substituted alkanyl, alkenyl, substituted alkenyl, arylalkanyl,substituted arylalkanyl, arylalkenyl, substituted arylalkenyl,cycloalkanyl, substituted cycloalkanyl, cycloheteroalkanyl, substitutedcycloheteroalkanyl, heteroarylalkanyl, and substitutedheteroarylalkanyl. In certain embodiments of a compound of Formula I, R⁵is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, benzyl, phenethyl, and styryl, where the arylring of the benzyl or styryl group is optionally substituted with one ormore substituents selected from halo, —CN, —NO₂, —OH, C₁₋₆ alkyl, andC₁₋₆ alkoxy.

In certain embodiments of a compound of Formula I, R⁵ is selected fromaryl, substituted aryl, heteroaryl, and substituted heteroaryl. Incertain embodiments of a compound of Formula I, R⁵ is selected from C₅₋₈aryl, and substituted C₅₋₈ aryl substituted with one or moresubstituents selected from halo, —CN, —NO₂, —OH, C₁₋₆ alkyl, and C₁₋₆alkoxy. In certain embodiments of a compound of Formula I, R⁵ isselected from phenyl and pyridyl which are optionally substituted withhalo, —OH, C₁₋₃ alkyl, and C₁₋₃ alkoxy.

In certain embodiments of a compound of Formula I, each R¹ and R² isindependently selected from hydrogen, alkanyl, substituted alkanyl,arylalkanyl, substituted arylalkanyl, cycloalkanyl, substitutedcycloalkanyl, cycloheteroalkanyl, substituted cycloheteroalkanyl, halo,heteroalkanyl, substituted heteroalkanyl, heteroarylalkanyl, andsubstituted heteroarylalkanyl. In certain embodiments of a compound ofFormula I, each R¹ and R² is independently selected from hydrogen,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andbenzyl.

In certain embodiments of a compound of Formula I, each R¹ and R² isindependently selected from hydrogen, aryl, substituted aryl,heteroaryl, and substituted heteroaryl. In certain embodiments of acompound of Formula I, each R¹ and R² is independently selected fromhydrogen and phenyl, wherein the phenyl group is optionally substitutedwith one or more substituents selected from halo, —CN, —NO₂, —OH, C₁₋₆alkyl, and C₁₋₆ alkoxy.

In certain embodiments of a compound of Formula I, each R¹ and R² isindependently selected from hydrogen, —OH, C₁₋₄ alkyl, and substitutedC₁₋₄ alkyl.

In certain embodiments of a compound of Formula I, each R¹ and R² isindependently selected from hydrogen, —OH, C₁₋₃ alkyl, and substitutedC₁₋₃ alkyl.

In certain embodiments of a compound of Formula I, each R¹ and R² ishydrogen.

In certain embodiments of a compound of Formula I, R⁶ is selected fromhydrogen and C₁₋₆ alkyl. In certain embodiments, R⁶ is hydrogen, and incertain embodiments, R⁶ is methyl.

In certain embodiments of a compound of Formula I, R³ and R⁴ areindependently selected from hydrogen, —C(O)OR⁷, and —C(O)R⁷.

In certain embodiments of a compound of Formula I, R⁷ is selected fromalkanyl, substituted alkanyl, cycloalkanyl, substituted cycloalkanyl,arylalkanyl, substituted arylalkanyl, heteroarylalkanyl, and substitutedheteroarylalkanyl. In certain embodiments, R⁷ is selected from methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and benzyl, wherein thearyl ring of the benzyl group is optionally substituted with one or moresubstituents selected from halo, CN, —NO₂, —OH, C₁₋₆ alkyl, and C₁₋₆alkoxy.

In certain embodiments of a compound of Formula I, R⁷ is selected fromaryl, substituted aryl, heteroaryl, and substituted heteroaryl. Incertain embodiments, R⁷ is selected from C₅₋₈ aryl, substituted C₅₋₈aryl, C₆₋₁₀ arylalkyl, and substituted C₆₋₁₀ arylalkyl. In certainembodiments, R⁷ is selected from phenyl, pyridyl, furyl, and thienyl,the aromatic rings of which are optionally substituted with one or moresubstituents selected from halo, —CN, —NO₂, —H, C₁₋₆ alkyl, and C₁₋₆alkoxy.

In certain embodiments of a compound of Formula I, R³ and R⁴ areindependently selected from hydrogen and —(CR⁸R⁹)OC(O)R¹⁰.

In certain embodiments of a compound of Formula I, R¹⁰ is selected fromhydrogen, C₁₋₁₀ alkyl, substituted C₁₋₁₀ alkyl, C₅₋₈ aryl, substitutedC₅₋₈ aryl, C₁₋₁₅ alkoxy, and substituted C₁₋₁₅ alkoxy.

In certain embodiments of a compound of Formula I, R⁸ and R⁹ areindependently selected from hydrogen, C₁₋₁₆ alkyl, substituted C₁₋₁₆alkyl, C₅₋₈ aryl, substituted C₅₋₈ aryl, C₆₋₁₀ arylalkyl, andsubstituted C₆₋₁₀ arylalkyl.

In certain other embodiments, compounds include levodopa prodrugs ofFormula (II):

a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein n is an integer from 2 to 4, R¹ is selected fromhydrogen, a straight chain C₁₋₃ alkyl, and a branched C₁₋₃ alkyl, and R⁵is selected from phenyl, and substituted phenyl wherein one or more ofthe substituents is selected from halo, —CN, —NO₂, —H, C₁₋₆ alkyl, andC₁₋₆ alkoxy. Certain embodiments of a compound of Formula (II) have thefollowing structures:

wherein R¹¹ is selected from hydrogen, halo, —CN, —NO₂, —OH, C₁₋₆ alkyl,and C₁₋₆ alkoxy.

In certain embodiments of a compound of Formula I, the compound isselected from:

-   2-Phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2-(4-Fluorophenylcarbonyloxy)ethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   3-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   3-(4-Fluorophenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2-Acetyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (2R)-2-Phenylcarbonyloxypropyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (2S)-2-Phenylcarbonyloxypropyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (2R)-2-(4-Fluorophenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (2S)-2-(4-Fluorophenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (1S)-1-Methyl-2-phenylcarbonyloxyethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (1R)-1-Methyl-2-(4-fluorophenylcarbonyloxy)ethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (1S)-1-Methyl-2-(4-fluorophenylcarbonyloxy)ethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (1S,2S)-1-Methyl-2-phenylcarbonyloxypropyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (1R,2R)-1-Methyl-2-(4-fluorophenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (1S,2S)-1-Methyl-2-(4-fluorophenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   3-(4-Methoxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   3-(2-Hydroxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   3-(4-Hydroxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2-Hydroxy-3-phenylcarbonyloxypropyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (2R)-2-(2-Hydroxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (2R)-2-(4-Hydroxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   (2R)-2-(4-Methoxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2-[(2-Hydroxyphenyl)carbonylamino]ethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2(R)-(3-Pyridylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2(S)-(3-Pyridylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2(R)-(4-Pyridylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2(S)-(4-Pyridylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2(R)-(2-Ethoxy-3-pyridylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2(S)-(2-Ethoxy-3-pyridylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2(R)-(2-Methyl-5-pyridylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate;-   2(S)-(2-Methyl-5-pyridylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate; and

pharmaceutically acceptable salts thereof.

In certain embodiments of the above compounds, the pharmaceuticallyacceptable salt is the hydrochloride salt.

Synthesis of Certain Compounds

Embodiments of levodopa prodrugs can be prepared by methods well knownin the art.

In certain embodiments the compounds can be prepared from readilyavailable starting materials using the following general methods andprocedures. It will be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures) are given, other process conditions canalso be used unless otherwise stated. Optimum reaction conditions canvary with the particular reactants or solvent used, but such conditionscan be determined by one skilled in the art by routine optimizationprocedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups can be used to prevent certain functionalgroups from undergoing undesired reactions. Suitable protecting groupsfor various functional groups as well as suitable conditions forprotecting and deprotecting particular functional groups are well knownin the art. For example, numerous protecting groups are described in T.W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis andreferences cited therein.

Furthermore, in certain embodiments, the levodopa prodrugs can containone or more chiral centers. Accordingly, such compounds can be preparedor isolated as pure stereoisomers, i.e., as individual enantiomers ordiastereomers, or as stereoisomer-enriched mixtures. All suchstereoisomers (and enriched mixtures) are included within the scope ofthe embodiments, unless otherwise indicated. Pure stereoisomers (orenriched mixtures) can be prepared using, for example, optically activestarting materials or stereoselective reagents well known in the art.Alternatively, racemic mixtures of such compounds can be separatedusing, for example, chiral column chromatography, chiral resolvingagents and the like.

In certain embodiments, levodopa prodrugs can be prepared by methodswell known in the art (see Greene et al., Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, 1999, and references citedtherein; Larock, Comprehensive Organic Transformations, John Wiley &Sons, Second Edition, 1999; March, Advanced Organic Chemistry, JohnWiley & Sons, Fourth Edition, 1992; Smith, Organic Synthesis, John Wiley& Sons, 1994; U.S. Pat. No. 4,966,915; U.S. Pat. No. 5,462,933. Thedisclosures of these references are herein incorporated by reference.

Some of the preparative methods can be found in Gallop et al. U.S.Patent Publication US 2002/0099041 and Gallop et al. InternationalPublication WO 02/28882.

A compound of Formula I can be prepared as illustrated in Scheme 1below. Reacting Boc-protected levodopa (2) with a halide of Formula (3)in the presence of an appropriate base such as alkali metal bicarbonateor carbonate followed by hydrolysis of the Boc protecting group underacidic conditions affords a compound of Formula (I).

Alternatively, reacting an appropriately protected levodopa derivative(4) with an alcohol (5) under standard coupling conditions (Scheme 2)followed by removal of the protecting groups provides a compound ofFormula (I).

As shown in Scheme 3, an epoxide of Formula (6) can react with an acidof Formula (7) in the presence of a phase transfer reagent such astetrabutylammonium bromide in an appropriate solvent (e.g.,acetonitrile, toluene etc.) at an appropriate elevated temperature suchas 50° C. to afford an alcohol of Formula (8), a compound of Formula(5), wherein Q is —X—C(O) and X is O.

Alternatively, a hydroxyamine HO(CR¹R²)_(n)NHR⁶ (11) can be coupled withacid of Formula (7) to provide a compound of Formula (5), wherein Q is—XC(O) and X is —NR⁶—.

Alternatively, a diol of Formula (9) can be converted to a compound ofFormula (10), which is further be coupled with a levodopa derivative ofFormula (4) to provide a silyl ether of Formula (11). Reacting a silylether of Formula (11) with hydrogen fluoride affords an alcohol ofFormula (12). Coupling of an alcohol of Formula (12) with an acid ofFormula (7) under appropriate conditions (e.g., DCC/DMAP/DCM) followedby removal of the protecting groups under conditions described aboveprovides a compound of Formula I (Scheme 4).

With appropriate manipulation and protection of the chemicalfunctionalities, synthesis of the remaining compounds of Formula (I) isaccomplished by methods analogous to those described above and in theexperimental section.

Therapeutic Uses of Certain Compounds

In accordance with certain embodiments, levodopa prodrugs are precursorsof dopamine. Thus, the levodopa prodrugs of Formula (I) can beadministered to a patient, such as a human, to treat Parkinson'sdisease. In certain embodiments, at least one levodopa prodrug can becoadministered with another therapeutic agent or drug, such as adecarboxylase inhibitor, or a prodrug thereof, which can act as aprotectant to inhibit or prevent premature decarboxylation of thelevodopa prodrug and/or the levodopa metabolite.

The levodopa prodrugs can be delivered from the same dosage form as thedecarboxylase inhibitor, or from a different dosage form. The levodopaprodrugs can be administered at the same time as, prior to, orsubsequent to, the administration of a decarboxylase inhibitor. Thelevodopa prodrugs, together with a decarboxylase inhibitor ordecarboxylase inhibitor prodrug or derivative, can be administered to apatient, such as a human, to treat Parkinson's disease.

Certain embodiments of compounds and compositions comprising at leastone levodopa prodrug together with at least one decarboxylase inhibitoror at least one decarboxylase inhibitor prodrug or derivative can beadvantageously used in human medicine. As disclosed herein, in certainembodiments, the compounds and compositions are useful for the treatmentof Parkinson's disease. When used to treat Parkinson's disease, levodopaprodrugs can be administered or applied in combination with adecarboxylase inhibitor such as carbidopa and/or a carbidopa prodrug, orbenserazide and/or a benserazide prodrug. Additionally, the therapeuticeffectiveness of the above combinations can be further enhanced byco-administration of another pharmaceutically active agent such as acatechol oxygen methyl transferase (COMT) inhibitor. Further, in certainembodiments, the levodopa prodrugs, can be administered to a patient,such as a human, together with (i) a decarboxylase inhibitor such ascarbidopa, benserazide or a prodrug thereof, and (ii) a pharmaceuticallyactive agent such as a catechol oxygen methyl transferase (COMT)inhibitor or prodrug thereof, to treat Parkinson's disease.

The levodopa prodrugs disclosed herein are particularly adapted for oraladministration, although they can also be administered by any otherconvenient route, such as for example, injection, infusion, inhalation,transdermal, absorption through epithelial or mucosal membranes (e.g.,oral, rectal and/or intestinal mucosa).

In certain embodiments, the compounds and/or compositions providelevodopa and levodopa prodrugs upon in vivo administration to a patient.The promoiety or promoieties of the levodopa prodrugs are currentlybelieved to be cleaved either chemically and/or enzymatically. One ormore enzymes, such as cholesterases, present in the stomach, intestinallumen, intestinal tissue, blood, liver, brain or any other suitabletissue of a mammal can enzymatically cleave the promoiety or promoietiesof the compounds and/or compositions. The mechanism of cleavage is notimportant to the embodiments.

The promoiety or promoieties of certain embodiments of the compoundsand/or compositions can be designed to be cleaved after absorption bythe gastrointestinal tract, for example in intestinal tissue, blood,liver or other suitable tissue of a mammal. In this situation, levodopaprodrugs can be absorbed into the systemic circulation from the smalland large intestines either by active transport, passive diffusion or byboth active and passive processes. In certain embodiments, levodopaprodrugs are actively transported across the intestinal endothelium byorganic cation transporters expressed throughout the gastrointestinaltract including the small intestine and colon. Certain compounds and/orcompositions of levodopa prodrugs can be administered as sustainedrelease systems. In certain embodiments, the compounds can be deliveredby oral sustained release administration. In some embodiments, thecompounds can be administered twice per day, in certain embodiments,once per day, and in certain embodiments at intervals greater than onceper day.

Certain levodopa prodrugs can be useful in treating Parkinsonism byadministration of one or more of the levodopa prodrugs together with adecarboxylase inhibitor such as carbidopa or a prodrug of carbidopa, incertain embodiments by the oral route, to a mammalian subject in need ofthe treatment. In a human subject weighing 70 kg, a levodopa prodrug canbe administered at a dose having an equivalent weight of levodoparanging from 10 mg to 10 g per day, and in certain embodiments, anequivalent weight of levodopa ranging from 100 mg to 3 g per day. Thedose can be adjusted by one skilled in the art based on several factors,e.g. the body weight and/or condition of the subject treated, the doseof the decarboxylase inhibitor or prodrug of a decarboxylase inhibitorbeing administered, the severity of the Parkinson's disease, and theincidence of side effects, the manner of administration and the judgmentof the prescribing physician. Dosage ranges can be determined by methodsknown to those skilled in the art.

The levodopa prodrugs can be assayed in vitro and in vivo, for thedesired therapeutic or prophylactic activity prior to use in humans. Forexample, in vitro assays can be used to determine whether administrationof a specific levodopa prodrug is a substrate of a transporter protein,including organic cation transporters such as OCTN1 and OCTN2. Examplesof certain assay methods applicable to analyzing the ability of aspecific levodopa prodrug to act as a substrate for a transporterprotein are disclosed in Zerangue et al. U.S. Appl. Publication2003/0158254. In vitro assays can also be used to determine whetheradministration of a specific levodopa prodrug is therapeuticallyeffective. Levodopa prodrugs can also be demonstrated to be effectiveand safe using animal model systems.

In certain embodiments, a therapeutically effective dose of a levodopaprodrug can provide therapeutic benefit without causing substantialtoxicity. Toxicity of levodopa prodrugs can be determined using standardpharmaceutical procedures and can be ascertained by the skilled artisan.The dose ratio between toxic and therapeutic effect is the therapeuticindex. Certain levodopa prodrugs can exhibit particularly hightherapeutic indices in treating diseases and disorders such asParkinson's disease. The dosage of a levodopa prodrug can be within arange of circulating concentrations that include a therapeuticallyeffective amount of levodopa prodrug with little or no toxicity.

In addition to the use of the levodopa prodrugs and compositionscomprising levodopa prodrugs of the present disclosure for treatingParkinson's disease, in certain embodiments the prodrugs andcompositions of the present disclosure can also be useful for treatingother dopamine-related diseases. Dopamine-related diseases can becharacterized by either insufficient or excessive functionaldopaminergic activity in the central nervous system. Examples of otherdopamine-related diseases include, but are not limited to, affectivedisorders such as depression and attention deficit disorder, psychoticdisorders such as schizophrenia and manic depression, cognitiveimpairment disorders, movement disorders such as restless legs syndrome,periodic limb movement disorders, tardive dyskinesia, hypertension,Huntington's disease, and Tourette's syndrome, addictive disorders,congestive heart failure, and excessive daytime sleepiness. For thetreatment of these diseases, a levodopa prodrug can be coadministeredwith an additional active agent. Therapeutically effective doses fortreating dopamine-related diseases can be determined by the methodsdisclosed herein for the treatment of Parkinson's disease and by methodsknown in the art.

Formulations of Certain Compounds

In some embodiments, levodopa prodrugs can be incorporated intopharmaceutical compositions to be administered orally. Oraladministration of such pharmaceutical compositions can result in uptakeof the levodopa prodrugs throughout the intestine and entry into thesystemic circulation. Such compositions can be prepared in a manner wellknown in the pharmaceutical art and comprise at least one levodopaprodrug. The present compositions can include a therapeuticallyeffective amount of at least one levodopa prodrug, in some embodiments,in purified form, together with a decarboxylase inhibitor such ascarbidopa, benserazide or a prodrug thereof, and a suitable amount of apharmaceutically acceptable vehicle, so as to provide an appropriateform for administration to a patient.

Certain embodiments also include compositions that comprise, as theactive ingredient, at least one of the levodopa prodrugs associated withpharmaceutically acceptable excipients, carriers, diluents and/oradjuvants. In forming the compositions, the active ingredient can bemixed with an excipient, diluted by a diluent or enclosed within acarrier, which can be in the form of a capsule, sachet, paper or othercontainer. When the excipient serves as a diluent, it can be a solid,semi-solid, or liquid material, which acts as a vehicle, carrier ormedium for the active ingredient. Thus, the compositions can be in theform of tablets, pills, powders, lozenges, sachets, cachets, elixirs,suspensions, emulsions, solutions, and syrups containing, for example,up to 90% by weight of the active compound using, for example, soft andhard gelatin capsules.

In preparing a composition, it can be useful to mill the active compoundto provide an appropriate particle size prior to combining with otheringredients. For example, if the active compound is substantiallyinsoluble, the active compound can be milled to a particle size of lessthan 200 mesh. If the active compound is substantially water soluble,the particle size of the active compound can be adjusted by milling toprovide a substantially uniform distribution in the formulation, e.g.about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Thecompositions can additionally include lubricating agents such as talc,magnesium stearate, and mineral oil, wetting agents, emulsifying andsuspending agents, preserving agents such as methyl- andpropylhydroxy-benzoates, sweetening agents, pH adjusting and bufferingagents, toxicity adjusting agents, flavoring agents, and the like. Thecompositions can be formulated so as to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient by employing procedures known in the art.

A composition can be formulated in unit dosage form, each dosagecomprising an equivalent weight of levodopa ranging from 10 mg to 10 g:“Unit dosage form” refers to a physically discrete unit suitable as aunitary dosage for humans and other mammals, each unit containing apredetermined quantity of active material calculated to produce thedesired therapeutic effect, in association with a suitablepharmaceutical excipient, diluent, carrier and/or adjuvant.

A levodopa prodrug can be administered in a therapeutically effectiveamount. It will be understood, however, that the amount of the compoundactually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient can be mixed with a pharmaceutical excipient, diluent,carrier and/or adjuvant to form a solid preformulation compositioncontaining a homogeneous mixture containing the levodopa prodrug. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the prodrug is dispersed evenly throughout the composition sothat the composition can be readily subdivided into equally effectiveunit dosage forms such as tablets, pills and capsules. This solidpreformulation can then be subdivided into unit dosage forms of the typedescribed herein comprising, for example, a equivalent weight oflevodopa ranging from 10 mg to 10 g.

Tablets or pills comprising a levodopa prodrug can be coated orotherwise compounded to provide a dosage form affording the advantage ofsustained release. For example, a tablet or pill can comprise an innerdosage and an outer dosage component, the latter being in the form of anenvelope over and/or enclosing the former. The two components can beseparated by an enteric layer. The enteric layer can serve to resistdisintegration in the stomach and permit the inner component to passintact into the duodenum, or to delay release. A variety of materialscan be used for such enteric layers or coatings. For example, suchmaterials include a number of polymeric acids and mixtures of polymericacids with such materials as shellac, cetyl alcohol, and celluloseacetate

The liquid forms in which the compositions comprising levodopa prodrugscan be incorporated for administration orally or by injection includeaqueous solutions suitably flavored syrups, aqueous or oil suspensions,and flavored emulsions with edible oils such as cottonseed oil, sesameoil, coconut oil, or peanut oil, as well as elixirs and similarpharmaceutical vehicles.

Sustained Release Oral Dosage Forms

Certain levodopa prodrugs can be practiced with a number of differentdosage forms, which can be adapted to provide sustained release of thelevodopa prodrug upon oral administration.

In certain embodiments, the dosage form can comprise beads that ondissolution or diffusion release the prodrug over an extended period ofhours, in some embodiments, over a period of at least 4 hours, in someembodiments, over a period of at least 8 hours, over a period of atleast 12 hours, over a period of at least 24 hours, and in otherembodiments, over a period of more than 24 hours. The prodrug-releasingbeads can have a central composition or core comprising a prodrug andpharmaceutically acceptable vehicles, including an optional lubricant,antioxidant and buffer. Suitable timed-release beads are disclosed inLu, Int. J. Pharm., 1994, 112, 117-124; Pharmaceutical Sciences byRemington, 14^(th) ed, pp. 1626-1628 (1970); Fincher, J. Pharm. Sci.,1968, 57, 1825-1835; and U.S. Pat. No. 4,083,949). Suitable tablets aredisclosed in Pharmaceutical Sciences by Remington, 17^(th) Ed, Ch. 90,pp. 1603-1625 (1985).

In certain embodiments, an oral sustained release pump can be used (seeLanger, 1990, Science, 249:1527-1533; Sefton, 1987, CRC Crit. Ref;Biomed. Eng., 14:201; Saudek et al., 1989, N. Engl. J. Med., 321:574).

In certain embodiments, polymeric materials can be used for oralsustained release delivery such as described, for example, in “MedicalApplications of Controlled Release,” Langer and Wise (eds.), CRC Press,Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,” Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Ranger and Peppas, 1983, J. Macromol. Sci. Rev. Macromol Chem., 23:61;Levy et al., 1985, Science, 228: 190; During et al., 1989, Ann. Neurol.,25:351; and Howard et al., 1989, J. Neurosurg., 71:105.

In certain embodiments, enteric-coated preparations can be used for oralsustained release administration. In certain embodiments, coatingmaterials include polymers with a pH-dependent solubility (i.e.,pH-controlled release), polymers with a slow or pH-dependent rate ofswelling, dissolution or erosion (i.e., time-controlled release),polymers that can be degraded by enzymes (i.e., enzyme-controlledrelease) and polymers that form firm layers that can be destroyed by anincrease in pressure (i.e., pressure-controlled release).

In certain embodiments, drug-releasing lipid matrices orprodrug-releasing waxes can be used for oral sustained releaseadministration.

In certain embodiments, a controlled-release system can be placed inproximity to the target of the levodopa prodrug, thus requiring only afraction of the systemic dose (see Goodson, in “Medical Applications ofControlled Release,” supra, vol. 2, pp. 115-138 (1984)). Othercontrolled-release systems discussed in Langer, 1990, Science,249:1527-1533 can also be used.

In certain embodiments, a dosage form can comprise a levodopa prodrugcoated on a polymer substrate. The polymer can be an erodible, or anonerodible polymer. Representative biodegradable polymers aredescribed, for example, in Rosoff, Controlled Release of Drugs, Chap. 2,pp. 53-95 (1989); and U.S. Pat. Nos. 3,811,444; 3,962,414; 4,066,747;4,070,347; 4,079,038; and 4,093,709.

In certain embodiments, a dosage form can comprise a levodopa prodrugloaded into a polymer that releases the prodrug by diffusion through apolymer, or by flux through pores or by rupture of a polymer matrix asdescribed, for example, in Coleman et al., Polymers, 1990, 31,1187-1231; Roerdink et al., Drug Carrier Systems, 1989, 9, 57-100; Leonget al., Adv. Drug Delivery Rev., 1987, 1, 199-233; Roff et al., Handbookof Common Polymers, 1971, CRC Press; and U.S. Pat. No. 3,992,518.

In certain embodiments, osmotic delivery systems can be used for oralsustained release administration (see Verma et al., Drug Dev. Ind.Pharm., 2000, 26:695-708).

Regardless of the specific form of sustained release oral dosage formused, a levodopa prodrug can be released from the dosage form, e.g., anorally administered dosage form, over a sufficient period of time toprovide prolonged therapeutic concentrations of levodopa in the blood ofa patient enabling administration of the dosage form on only a once ortwice per day basis. In certain embodiments, the levodopa prodrug canmaintain a therapeutic or prophylactic blood concentration of levodopaor levodopa prodrug in the systemic circulation of a patient followingoral administration of a levodopa prodrug over a period of at least 4hours, in certain embodiments, over a period of at least 8 hours, and incertain embodiments, over a period of at least 12 hours.

The compositions can be administered for prophylactic and/or therapeutictreatments. A therapeutic amount is an amount sufficient to remedy adisease state or symptoms, or otherwise prevent, hinder, retard, orreverse the progression of disease or any other undesirable symptoms inany way whatsoever. In prophylactic applications, compositions areadministered to a patient susceptible to or otherwise at risk of aparticular disease or infection. Hence, a prophylactically effectiveamount is an amount sufficient to prevent, hinder or retard a diseasestate or its symptoms. The precise amount of at least one compoundcontained in a composition can depend on a patient's state of health andweight.

An appropriate dosage of the pharmaceutical composition can bedetermined according to any one of several well-established protocols.For example, animal studies, such as studies using mice or rats, can beused to determine an appropriate dose of a pharmaceutical compound. Theresults from animal studies can be extrapolated to determine doses foruse in other species, such as for example, humans.

In certain embodiments, the dosage forms can be administered twice perday, in some embodiments once per day, and in some embodiments, atlonger intervals.

Certain embodiments can be further defined by reference to the followingexamples, which describe in detail preparation of compounds andcompositions comprising at least one levodopa prodrug and assays forusing compounds and compositions comprising at least one levodopaprodrug. It will be apparent to those skilled in the art that manymodifications, both to materials and methods, can be practiced withoutdeparting from the embodiments.

EXAMPLES

The following synthetic and biological examples are offered toillustrate certain embodiments and are not to be construed in any way aslimiting the scope. Unless otherwise stated, all temperatures are indegrees Celsius. In the examples below, the following abbreviations havethe following meanings. If an abbreviation is not defined, it has itsgenerally accepted meaning.

-   -   Boc=tert-butyloxycarbonyl    -   DCC=dicyclohexylcarbodiimide    -   DCM=dichloromethane    -   DMAP=4-N,N-dimethylaminopyridine    -   EDTA=ethylenediaminetetraacetic acid    -   g=gram    -   hr=hour    -   HPLC=high pressure liquid chromatography    -   L=liter    -   LC/MS=liquid chromatography/mass spectroscopy    -   M=molar    -   mg=milligram    -   min minute    -   mL=milliliter    -   mmol=millimoles    -   Pd—C=palladium on activate carbon    -   THF=tetrahydrofuran    -   μg=microgram    -   μL=microliter    -   μM=micromolar

Example 1 1(R)- and 1(S)-Cyclohexyloxycarbonylethyl2(S)-amino-3-(3,4-dihydroxyphenyl)-propanoate

To a mixture of cyclohexanol (10.9 g, 10.9 mmol), pyridine (8.62 g, 10.9mmol) in dichloromethane was added 2-bromopropionyl chloride (18.53 g,10.9 mmol) at 0° C. The resulting mixture was stirred at roomtemperature for 1 hr. The product was partitioned between hexane and 10%citric acid. The organic phase was separated, dried over MgSO₄ andconcentrated to yield 2-bromo-propionic acid cyclohexyl ester, which wasused in the following reaction without further purification.

To a suspension of compound Boc-DOPA (297 mg, 1 mmol) and cesiumhydrogencarbonate (194 mg, 1 mmol) in acetone was added2-bromo-propionic acid cyclohexyl ester (235 mg, 1 mmol) and theresulting mixture was stirred at 55° C. for 40 hrs. After removing thesolvent, the residue was partitioned between ethyl acetate and 10%citric acid. The organic phase was separated, dried over MgSO₄, andconcentrated. The resulting residue was then treated with 30%trifluoroacetic acid in dichloromethane at room temperature for 30 min.After removing the solvent, the resulting residue was purified byreverse phase preparative HPLC to afford 40 mg of a mixture of twodiastereoisomers of the title compounds. MS (ESI) m/z 352.73 (M+H)⁺.

Example 2 1(R)- and 1(S)-Isoproxycarbonylethyl2(S)-amino-3-(3,4-dihydroxy-phenyl)-propanoate

Following the procedure described in Example 1, and substitutingcyclohexanol with isopropanol, provided a mixture of twodiastereoisomers of the title compound. MS (ESI) m/z 312.70 (M+H⁺)⁺.

Example 3 2-Phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step ABromoethyl benzoate

To a solution of benzoic acid (2.44 g, 20 mmol) and 2-bromoethan-1-ol(1.42 mL, 20 mmol) in 40 mL of anhydrous dichloromethane, a solution of1,3-dicyclohexylcarbodiimide (4.12 g, 20 mmol) in dichloromethane wasslowly added followed by addition of a catalytic amount of4-(dimethylamino)pyridine. The resulting mixture was stirred at roomtemperature for 16 hrs. After filtration, the filtrate was washed with5% NaHCO₃, brine, and dried over Na₂SO₄. After removing the solvent,chromatography (silica gel, 10% ethyl acetate in hexane) of the residuegave 3.7 g (82%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ 3.62(t, J=6 Hz, 2H), 4.60 (t, J=6 Hz, 2H), 7.42 (m, 2H), 7.54 (m, 2H), 8.04(m, 2H).

Step B 2-Phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

A suspension of bromoethyl benzoate (2.29 g, 10 mmol), N-Boc-L-DOPACOOH(3.2 g, 11 mmol), and cesium bicarbonate (2.1 g, 11 mmol) inN,N-dimethylacetamide (50 mL) was stirred at 55° C. for 16 hrs. Thesolvent was evaporated under vacuum. The resulting residue was dissolvedin ethyl acetate, washed with water, 5% NaHCO₃, brine, and dried overNa₂SO₄. After removing the solvent, chromatography (silica gel, 30%ethyl acetate in hexane) of the residue gave 3.8 g of a white solid. Thewhite solid was treated with 4M HCl in dioxane at room temperature for30 min. After removing the solvent, the resulting solid was dissolved in10 mL of anhydrous acetonitrile and refrigerated. The resulting whiteprecipitate was filtered, washed with ether, and dried under vacuum toafford 2.2 g (58%) of the title compound. ¹H NMR (400 MHz, CD₃OD): δ3.02 (dd, J=7.2, 14.4 Hz, 1H), 3.11 (dd, J=5.6, 14.4 Hz, 1H), 4.25 (t,J=6.4 Hz, 1H), 4.52-4.64 (m, 4H), 6.53 (dd, J=2, 8 Hz, 1H), 6.67 (d, J=2Hz, 1H), 6.69 (d, J=8 Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.60 (t, J=7.6Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI) m/z 346.17 (M+H)⁺ and 344.13(M−H)⁻.

Example 4 2-(4-Fluorophenylcarbonyloxy)ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 3 and substituting benzoicacid with 4-fluorobenzoic acid, provided the title compound (62% over 2steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 3.03 (dd, J=6.8,14.4 Hz, 1H), 3.11 (dd, J=6, 14.4 Hz, 1H), 4.26 (t, J=6.4 Hz, 1H),4.50-4.63 (m, 4H), 6.53 (dd, J=2, 8 Hz, 1H), 6.67 (d, J=2 Hz, 1H), 6.69(d, J=8 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 8.05 (dd, J=5.2, 8.8 Hz, 2H).MS (ESI) m/z 363.92 (M+H)⁺ and 362.02 (M−H)⁻.

Example 5 3-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 3 and substituting2-bromoethan-1-ol with 3-bromopropan-1-ol provided the title compound(61% over 2 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 2.40 (m,2H), 3.02 (dd, J=7.2, 14.4 Hz, 1H), 3.09 (dd, J=6.4, 14.4 Hz, 1H), 4.20(t, J=6.4 Hz, 1H), 4.35 (t, J=6.4 Hz, 1H), 4.37 (t, J=6.4 Hz, 1H), 6.53(dd, J=2, 8 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 6.73 (d, J=8 Hz, 1H), 7.48(t, J=8 Hz, 2H), 7.61 (t, J=8.0 Hz, 1H), 8.01 (m, 2H). MS (ESI) m/z360.13 (M+H)⁺ and 358.06 (M−H)⁻.

Example 6 3-(4-Fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 3 substituting benzoic acidwith 4-fluorobenzoic acid and 2-bromoethan-1-ol with 3-bromopropan-1-olrespectively, provided the title compound (55% over 2 steps) as a whitesolid. ¹H NMR (400 MHz, CD₃OD): δ 2.12 (m, 2H), 3.03 (dd, J=7.2, 14.4Hz, 1H), 3.09 (dd, J=6.4, 14.4 Hz, 1H), 4.21 (t, J=7.2 Hz, 1H), 4.35 (t,J=6.4 Hz, 2H), 4.37 (t, J=6.4 Hz, 2H), 6.54 (dd, J=2, 8 Hz, 1H), 6.67(d, J=2 Hz, 1H), 6.73 (d, J=8 Hz, 1H), 7.21 (t, J=8.8 Hz, 2H), 8.07 (dd,J=5.6, 8.8 Hz, 2H). MS (ESI) m/z 378.27 (M+H)⁺ and 376.24 (M−H)⁻.

Example 7 2-Acetyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure step 2 described in Example 3 and substitutingof 2-bromoethyl with 2-bromoethyl acetate, provided the title compound,which was purified by using HPLC (0.05% formic acid/water/acetonitrile)followed by lyophilization in the presence of hydrochloride. ¹H NMR (400MHz, CD₃OD): δ 2.50 (s, 3H), 3.03 (dd, J=6.8, 14.4 Hz, 1H), 3.11 (dd,J=6.4, 14.4 Hz, 1H), 4.24 (t, J=6.4 Hz, 1H), 4.27 (t, J=7.2 Hz, 2H),4.44 (m, 2H), 6.55 (dd, J=2, 8 Hz, 1H), 6.67 (d, J=2 Hz, 1H), 6.73 (d,J=8 Hz, 1H). MS (ESI) m/z 284.10 (M+H)⁺ and 282.13 (M−H)⁻.

Example 8 (2R)-2-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step A(2R)-1-(tert-Butyldimethyl-1-silyloxy)propan-2-ol

(R)-(−)-1,2-propanediol (5 g, 65.7 mmol) and imidazole (4.47 g, 65.7mmol) was dissolved in anhydrous dichloromethane (40 mL). A solution oftert-butyldimethylchlorosilane (9.9 g, 65.7 mmol) in dichloromethane wasadded at 0° C. The mixture was stirred at 0° C. for 2 hrs. Afterfiltration the filtrate was dried over Na₂SO₄ and concentrated to afford12.5 g (100%) of the title compound, which was used in the next reactionstep without further purification. ¹H NMR (400 MHz, CDCl₃): δ 0 (s, 6H),0.83 (s, 9H), 1.04 (d, J=6.4 Hz, 3H), 2.64 (s, br, 1H), 3.26 (dd, J=8,9.6 Hz, 1H), 3.50 (dd, J=3.2, 9.6 Hz, 1H), 3.74 (m, 1H).

Step B (1R)-1-Methyl-2-(tert-butyldimethylsilyloxy)ethyl benzoate

Benzoic acid (2.44 g, 20 mmol) and (2R)-1-(tert-butyldimethyl-17silyloxy)propan-2-ol (4.18 g, 22 mmol) was dissolved in 40 μL ofanhydrous dichloromethane. A solution of 1,3-dicyclohexylcarbodiimide(4.94 g, 24 mmol) in dichloromethane was added slowly, followed by acatalytic amount of 4-(dimethylamino)pyridine. The mixture was stirredat room temperature for 16 hrs. After filtration, the filtrate waswashed with 5% NaHCO₃, brine, and dried over Na₂SO₄. After removing thesolvent, chromatography (silica gel, 10% ethyl acetate in hexane) of theresidue provided 5.8 g (98%) of the title compound. ¹H NMR (400 MHz,CDCl₃): δ 0 (s, 3H), 0.2 (s, 3H), 0.83 (s, 9H), 1.30 (d, J=6.4 Hz, 1H),3.66 (dd, J=4.8, 10.8 Hz, 1H), 3.72 (dd, J=5.6, 10.8 Hz, 1H), 5.15 (m,1H), 7.36 (t, J=8.4 Hz, 2H), 7.48 (t, J=8.4 Hz, 1H), 7.98 (d, J=8.4 Hz,2H).

Step C (1R)-2-Hydroxy-isopropyl benzoate

(1R)-1-methyl-2-(tert-butyldimethylsilyloxy)ethyl benzoate (5.8 g, 19.7mmol) was dissolved in anhydrous tetrahydrofuran. Triethylaminetrihydrofluoride was added slowly. The mixture was stirred at roomtemperature for 8 hrs, and the solvent was evaporated under reducedpressure. Chromatography (silica gel, 30% ethyl acetate in hexane) ofthe residue provided 3.2 g (90%) of the title compound. ¹H NMR (400 MHz,CDCl₃): δ 1.37 (d, J=6.4 Hz, 1H), 2.30 (t, J=6.4 Hz, 1H), 3.78 (m, 1H),5.23 (m, 1H), 7.42 (t, J=7.6 Hz, 2H), 7.54 (t, J=7.6 Hz, 1H), 8.03 (d,J=7.6 Hz, 2H).

Step D (1R)-2-Bromo-isopropyl benzoate

To a suspension of dibromotriphenylphosphorane (9 g, 21.3 mmol) inanhydrous dichloromethane, a solution of (1R)-2-hydroxyisopropylbenzoate (3.2 g, 17.7 mmol) in dichloromethane was added slowly at 0° C.The mixture was stirred at 0° C. to room temperature for 16 hrs, thenwashed with water, 5% NaHCO₃, brine, and dried over Na₂SO₄. Afterconcentration, hexane was added to the resulting residue. Ph₃PO wasprecipitated. After filtration and thoroughly washing with hexane, thefiltrate was concentrated. Chromatography of the residue with silica geleluting with 10% ethyl acetate in hexane afforded 3.6 g (85%) of thetitle compound. ¹H NMR (400 MHz, CDCl₃): δ 1.47 (d, J=6.4 Hz, 3H), 3.75(m, 2H), 5.31 (m, 1H), 7.42 (t, J=8 Hz, 2H), 7.54 (t, J=8 Hz, 1H), 8.04(d, J=8 Hz, 2H).

Step F (2R)-2-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

A suspension of (1R)-2-bromoisopropyl benzoate (4.98 g, 20.6 mmol),N-Boc-L-DOPA-COOH (7.3 g, 25 mmol), and cesium bicarbonate (4.85 g, 25mmol) in N,N-dimethylacetamide (100 mL) was stirred at 55° C. for 16hrs. The solvent was evaporated under vacuum. To the residue was addedethyl acetate and the resulting solution was washed with water, 5%NaHCO₃, brine, and dried over Na₂SO₄. After removing the solvent underreduced pressure, chromatography (silica gel, 30% ethyl acetate inhexane) of the residue gave 6.3 g (68%) of a white solid. The whitesolid was treated with 50 mL of 4M HCl in dioxane at room temperaturefor 30 min. The reaction mixture was concentrated to dryness underreduced pressure. The resulting residue was dissolved in about 20 mL ofanhydrous acetonitrile and 4 mL of ether. The solution was refrigerated,and the resulting white precipitate was filtered, washed with ether, anddried under vacuum to afford 4.7 g (87%) of the title compound. ¹H NMR(400 MHz, CD₃OD): δ 1.40 (d, J=6.4 Hz, 3H), 2.99 (dd, J=7.6, 14.4 Hz,1H), 3.10 (dd, J=5.6, 14.4 Hz, 1H), 4.24 (dd, J=6, 8 Hz, 1H), 4.38 (dd,J=6.8, 11.6 Hz, 1H), 4.52 (dd, J=3.2, 11.6 Hz, 1H), 5.40 (m, 1H), (1H,dd, J=2, 8 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 7.47 (t,J=7.6 Hz, 2H), 7.60 (t, J=7.6 Hz, 1H), 8.02 (d, J=7.6 Hz, 2H). MS (ESI)m/z 360.15 (M+H)⁺ and 358.09 (M−H)⁻.

Example 9 (2S)-2-Phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 8, and substituting(R)-(−)-1,2-dipropanediol with (S)-(+)-1,2-dipropanediol, provided thetitle compound (32% over 5 steps) as a white solid. ¹H NMR (400 MHz,CD₃OD): δ 1.37 (d, J=6.4 Hz, 3H), 2.94 (dd, J=7.2, 14.4 Hz, 1H), 3.05(dd, J=6, 14.4 Hz, 1H), 4.23 (t, J=6.4 Hz, 1H), 4.40 (dd, J=5.2, 11.6Hz, 1H), 4.47 (dd, J=3.6, 11.6 Hz, 1H), 5.40 (m, 1H), 6.48 (dd, J=2, 8Hz, 1H), 6.64 (d, J=2 Hz, 1H), 6.69 (d, J=8 Hz, 1H), 7.47 (t, J=8 Hz,2H), 7.60 (t, J=7.2 Hz, 1H), 8.00 (d, J=8 Hz, 2H). MS (ESI) m/z 360.33(M+H)⁺ and 358.31 (M−H)⁻.

Example 10 (2R)-2-(4-Fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 8 and substituting benzoicacid with 4-fluorobenzoic acid, provided the title compound (23% over 5steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.38 (d, J=6.4 Hz,3H), 3.01 (dd, J=7.2, 14.4 Hz, 1H), 3.09 (dd, J=5.6, 14.4 Hz, 1H), 4.23(t, J=6.4 Hz, 1H), 4.37 (dd, J=6.4, 11.6 Hz, 1H), 4.49 (dd, J=3.2, 11.6Hz, 1H), 5.36 (m, 1H), 6.53 (dd, J=2, 8 Hz, 1H), 6.67 (d, J=2 Hz, 1H),6.69 (d, J=8 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 8.05 (dd, J=5.6, 8.8 Hz,2H). MS (ESI) m/z 378.11 (M+H)⁺ and 376.06 (M−H)⁻.

Example 11 (2S)-2-(4-Fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 8 substituting benzoic acidwith 4-fluorobenzoic acid and (R)-(−)-1,2-propanediol with(s)-(+)-1,2-propanediol separately, provided the title compound (43%over 5 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.36 (d,J=6.4 Hz, 3H), 2.96 (dd, J=7.2, 14.4 Hz, 1H), 3.05 (dd, J=6, 14.4H, 1Hz), 4.24 (dd, J=6, 6.8 Hz, 1H), 4.38 (dd, J=6.8, 11.6 Hz, 1H), 4.46(dd, J=3.2, 11.6 Hz, 1H), 5.38 (m, 1H), 6.49 (dd, J=2, 8 Hz, 1H), 6.64(d, J=2 Hz, 1H), 6.71 (d, J=8 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 8.05 (dd,J=5.6, 8.8 Hz, 2H). MS (ESI) m/z 378.48 (M+H)⁺ and 376.34 (M−H)⁻.

Example 12 (1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step A(2R)-1-(tert-Butyldimethyl-1-silyloxy)propan-2-ol

(R)-(−)-1,2-propanediol (5 g, 65.7 mmol) and imidazole (4.47 g, 65.7mmol) was dissolved in anhydrous dichloromethane. A solution ofchlorodimethyl-t-butylsilane (9.9 g, 65.7 mmol) in dichloromethane wasadded at 0° C. The mixture was stirred at 0° C. for 2 hrs. Afterfiltration the filtrate was dried over Na₂SO₄. Concentration gave 12.5 g(100%) of (2R)-1-(tert-Butyldimethyl-1-silyloxy)propan-2-ol, which wasused in the next reaction without further purification. ¹H NMR (400 MHz,CDCl₃): δ 0 (s, 6H), 0.83 (s, 9H), 1.04 (d, J=6.4 Hz, 3H), 2.64 (s, br,1H), 3.26 (dd, J=8, 9.6 Hz, 1H), 3.50 (dd, J=3.2, 9.6 Hz, 1H), 3.74 (m,1H).

Step B (1R)-1-Methyl-2-(tert-butyldimethylsilyloxy)ethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate

N-Boc-L-DOPA(OBn)2-COOH (3.6 g, 7.5 mmol) was dissolved in anhydrousdichloromethane. Triethylamine (2.6 mL, 18.5 mmol), and2,4,6-trichlorobenzoyl chloride (1.4 mL, 9 mmol), were added and thesolution stirred for 30 min. A solution of(2R)-1-(tert-butyldimethyl-1-silyloxy)propan-2-ol (1.7 g, 9 mmol) indichloromethane was slowly added to the reaction mixture, followed bythe addition of a catalytic amount of 4-(dimethylamino)pyridine. Theresulting mixture was stirred at room temperature for 16 hrs, thenwashed with 10% citric acid, dried over Na₂SO₄, and concentrated.Chromatography (silica gel, 10% ethyl acetate in hexane) afforded 3.4 g(70%) of (1R)-1-Methyl-2-(tert-butyldimethylsilyloxy)ethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate.¹H NMR (400 MHz, CDCl₃): δ 0.08 (s, 6H), 0.88 (s, 9H), 1.12 (d, J=6.4Hz, 3H), 1.42 (s, 9H), 2.99 (m, 2H), 3.35 (m, 1H), 3.59 (m, 1H), 3.84(m, 1H), 4.50 (m, 1H), 4.89 (d, NH, 1H), 5.10 (s, 4H), 6.60 (d, J=8 Hz,1H), 6.71 (s, 1H), 6.87 (d, J=8 Hz, 1H), 7.26-7.43 (m, 10H).

Step C (1R)-2-Hydroxy-isopropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate

(1R)-1-Methyl-2-(tert-butyldimethylsilyloxy)ethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate(3.4 g, 5.2 mmol) was dissolved in anhydrous tetrahydrofuran.Triethylamine trihydrofluoride was added slowly. The mixture was stirredat room temperature for 4 hours, and the solvent was evaporated underreduced pressure. Chromatography (silica gel, 30% ethyl acetate inhexane) provided 2.5 g (90%) of (1R)-2-Hydroxy-isopropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate.¹H NMR (400 MHz, CDCl₃): δ 1.09 (d, J=6.4 Hz, 3H), 1.41 (s, 9H), 2.78(s, br, 1H), 2.96 (m, 2H), 3.51 (m, 1H), 3.59 (m, 1H), 4.34 (m, 1H),4.98 (m, 1H), 5.05 (d, NH, 1H), 5.10 (s, 4H), 6.66 (d, J=8 Hz, 1H), 6.77(s, 1H), 6.83 (d, J=8 Hz, 1H), 7.26-7.43 (m, 10H).

Step D (1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate

To a solution of benzoic acid (0.57 g, 4.67 mmol) and(1R)-2-hydroxy-isopropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate(2.5 g, 4.67 mmol) was dissolved in 60 mL of anhydrous dichloromethanewas slowly added a solution of 1,3-dicyclohexylcarbodiimide (1.15 g, 5.6mmol) in dichloromethane followed by a catalytic amount of4-(dimethylamino)pyridine. The resulting mixture was stirred at roomtemperature for 16 hrs. After filtration, the filtrate was washed with5% NaHCO₃ and dried over Na₂SO₄. After removing the solvent,chromatography (silica gel, 10% ethyl acetate in hexane) of the residueprovided 2.6 g (87%) of (1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate.¹H NMR (400 MHz, CDCl₃): δ 1.23 (d, J=6.4 Hz, 3H), 1.41 (s, 9H), 2.98(m, 2H), 4.26 (m, 1H), 4.33 (m, 1H), 4.51 (m, 1H), 4.93 (d, NH, 1H),5.10 (s, 4H), 5.24 (m, 1H), 6.65 (d, J=8 Hz, 1H), 6.76 (s, 1H), 6.81 (d,J=8 Hz, 1H), 7.25-7.45 (m, 12H), 7.54 (t, J=7.6 Hz, 1H), 8.00 (d, J=7.6Hz, 2H).

Step E (1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate

To a solution of (1R)-1-methyl-2-phenylcarbonyloxyethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate(2.6 g, 4.85 mmol) in 40 mL of tetrahydrafuran was added 200 mg of 10%Pd—C pre-mixed with 10 mL of methanol under a nitrogen atmosphere. Theresulting mixture was stirred under hydrogen at room temperature for 2hrs. After filtration and washing with methanol, the filtrate wasconcentrated and chromatography of the residue (silica gel, 30% ethylacetate in hexane) afforded 1.87 g (100%) of(1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate.MS (ESI) m/z 460.20 (M+H)⁺ and 458.17 (M−H)⁻.

Step F (1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

(1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate(1.87 g, 4 mmol) was dissolved in 40 mL of 4M HCl in dioxane. Theresulting mixture was stirred at room temperature for 30 min. Dioxanewas evaporated completely under reduced pressure. The resulting whitesolid was dissolved in acetonitrile (5 mL), and ether added until thesolution became slightly cloudy. The solution was refrigerated overnightand the product was crystallized. The white crystalline solid wascollected and dried under vacuum to afford 1.5 g (93%) of the titlecompound. ¹H NMR (400 MHz, CD₃OD): δ 1.35 (d, J=6.4 Hz, 3H), 3.01 (dd,J=6.8, 14.4 Hz, 1H), 3.08 (dd, J=6.4, 14.4 Hz, 1H), 4.19 (t, J=6.4 Hz,1H), 4.34 (dd, J=6, 12.4 Hz, 1H), 4.49 (dd, J=2.8, 12.4 Hz, 1H), 5.35(m, 1H), 6.55 (dd, J=2, 8 Hz, 1H), 6.66 (d, J=−2 Hz, 1H), 6.71 (d, J=8Hz, 1H), 7.48 (t, J=7.2 Hz, 2H), 7.61 (t, J=7.2 Hz, 1H), 8.02 (d, J=7.6Hz, 2H). MS (ESI) m/z 360.16 (M+H)⁺ and 358.13 (M−H)⁻.

Alternatively, (1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate(Step D in Example 12) can be prepared as follows

Step A Epoxide Opening Method (2R)-2-Hydroxypropyl benzoate

A solution of (R)-(+)-propylene oxide (10.5 mL, 150 mmol), benzoic acid(12.2 g, 100 mmol), and tetrabutylammonium bromide (3.22 g, 10 mmol) inanhydrous acetonitrile was heated to 50° C. in a sealed pressure vesselfor 24 hrs. The reaction mixture was concentrated to dryness underreduced pressure, diluted with ethyl acetate, and washed with watertwice followed by the addition of saturated NaHCO₃ solution and brine.The organic layer was dried through MgSO₄ and concentrated under reducedpressure to afford 18.0 g (100%) of a mixture of (2R)-2-Hydroxypropylbenzoate and its regio-isomer (1R)-2-Hydroxy-isopropyl benzoate with aratio of 7.2:1. A solution of the mixture of regio-isomers (1.8 g, 10mmol) and 2,4,6-collidine (1.1 mL, 8 mmol) in 50 mL of anhydrousdichloromethane was cooled to −78° C. before acetyl chloride (0.28 mL, 4mmol) was added dropwise. The reaction mixture was stirred at −78° C.for 3 hrs before being warmed to room temperature over 1 h. The reactionmixture was diluted with dichloromethane and washed three times with0.5N HCl followed by the addition of brine. The organic layer was driedthrough MgSO₄ and concentrated under reduced pressure. Chromatography(silica gel, 1:2.5 ethyl acetate/hexane) afforded 1.6 g (89%) of(2R)-2-Hydroxypropyl benzoate.

Step A Diol Benzoylation Method (2R)-2-Hydroxypropyl benzoate

Benzoyl chloride (10.98 mL, 94.62 mmol) was added dropwise to a solutionof (R)-(−)-1,2-propanediol (6.00 g, 78.85 mmol) and 2,4,6-collidine(7.22 mL, 54.67 mmol) in 100 mL of anhydrous dichloromethane at −78° C.The reaction was stirred at −78° C. for three hours and at roomtemperature for 1 hr, before quenching with water (10 mL) for 15minutes. The quenched mixture was washed with 0.5N HCl (4×50 mL) untilthe dark color diminished, and then with saturated NaHCO₃ solution (4×50mL) and brine. The organic layer was separated, dried over Na₂SO₄ andconcentrated. Chromatography (silica gel 230-400 Mesh, 1:9 ethylacetate/Hexane) of the residue afforded 8.9 g (63%) of(2R)-2-Hydrpxypropyl benzoate as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 1.13 (d, J=6.4 Hz, 3H), 3.93 (m, 1H), 4.10 (m, 2H), 4.95 (d,J=4.8 Hz, 1H), 7.51 (t, J=7.2 Hz, 2H), 7.64 (t, J=7.6 Hz, 1H), 7.99 (d,J=6.8 Hz, 2H); MS (ESI) m/z 181 (M+H)⁺.

Step B (1R)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate

To a solution of(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoicacid (15.9 g, 33.3 mmol), (2R)-2-hydroxypropyl benzoate (5.0 g, 27.7mmol), and 4-(dimethylamino)pyridine (340 mg) in 250 mL of anhydrousdichloromethane, 1-(3-dimethylaminopropyl)3-ethylcarbodiimidehydrochloride (EDAC) (8.0 g, 41.6 mmol) was slowly added. The resultingmixture was stirred at room temperature for 16 hrs. The reaction mixturewas diluted with dichloromethane and washed with 0.5N HCl twice,followed by the addition of brine. The organic layer was separated,dried through a MgSO₄ pad and concentrated under reduced pressure.Chromatography (silica gel, 1:5 then 1:4 ethyl acetate/hexane) of theresidue followed by crystallization from 1:5 ethyl acetate/hexaneafforded 8.0 g (45%) of the title compound.

Example 13 (1S)-1-Methyl-2-phenylcarbonyloxyethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 12 and substituting(R)-(−)-1,2-propanediol with (S)-(+)-1,2-propanediol, provided the titlecompound (41% over 6 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ1.41 (d, J=6.4 Hz, 3H), 2.92 (dd, J=8, 14.8 Hz, 1H), 3.10 (dd, J=5.2,14.8 Hz, 1H), 4.23 (t, J=6.4 Hz, 1H), 4.38 (dd, J=7.2, 12.4 Hz, 1H),4.47 (dd, J=3.2, 12.4 Hz, 1H), 5.42 (m, 1H), 6.51 (dd, J=2, 8 Hz, 1H),6.65 (d, J=2 Hz, 1H), 6.67 (d, J=8 Hz, 1H), 7.47 (t, J=8.8 Hz, 2H), 7.60(t, J=8.8 Hz, 1H), 8.02 (m, 2H). MS (ESI) m/z 360.21 (M+H)⁺ and 358.13(M−H)⁻.

Example 14 (1R)-1-Methyl-2-(4-fluorophenylcarbonyloxy)ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 12 and substituting benzoicacid with 4-fluorobenzoic acid, provided the title compound (33% over 6steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.34 (d, J=6.4 Hz,3H), 3.04 (dd, J=6.8, 14.4 Hz, 1H), 3.08 (dd, J=5.6, 14.4 Hz, 1H), 4.20(t, J=6.4 Hz, 1H), 4.32 (dd, J=6, 11.6 Hz, 1H), 4.48 (dd, J=3.2, 11.6Hz, 1H), 5.36 (m, 1H), 6.55 (dd, J=2, 8 Hz, 1H), 6.68 (d, J=2 Hz, 1H),6.74 (d, J=8 Hz, 1H), 7.22 (t, J=8.8 Hz, 2H), 8.05 (dd, J=5.6, 8.8 Hz,2H). MS (ESI) m/z 378.11 (M+H)⁺ and 376.03 (M−H)⁻.

Example 15 (1S)-1-Methyl-2-(4-fluorophenylcarbonyloxy)ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 12, substituting benzoicacid with 4-fluorobenzoic acid and (R)-(−)-1,2-propanediol with(S)-(+)-1,2-propanediol, provided the title compound (46% over 6 steps)as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.41 (d, J=6.4 Hz, 3H),2.94 (dd, J=7.6, 14.4 Hz, 1H), 3.08 (dd, J=6, 14.4 Hz, 1H), 4.20 (t,J=7.2 Hz, 1H), 4.36 (dd, J=6.8, 11.2 Hz, 1H), 4.46 (dd, J=2.8, 11.2 Hz,1H), 5.41 (m, 1H), 6.51 (dd, J=2, 8 Hz, 1H), 6.66 (d, J=2 Hz, 1H), 6.72(d, J=8 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 8.04 (dd, J=5.6, 8.8 Hz, 2H).MS (ESI) m/z 378.16 (M+H)⁺ and 376.10 (M−H)⁻.

Example 16 (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step A(1R,2R)-2-Hydroxy-1-methylpropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate

N-Boc-L-DOPA(OBn)₂COOH (4.3 g, 9 mmol) was dissolved in anhydrousdichloromethane. Triethylamine (3 mL, 22 mmol), and2,4,6-trichlorobenzoyl chloride (1.7 mL, 11 mmol) were added and thesolution stirred for 30 min. A solution of (2R,3R-(−)-2,3-butanediol(1.0 mL, 11 mmol) in dichloromethane was slowly added to the reactionmixture followed by the addition of a catalytic amount of4-(dimethylamino)pyridine. The resulting mixture was stirred at roomtemperature for 16 hours, then washed with 10% citric acid, 5% NaHCO₃,brine, and dried over Na₂SO₄. After removing the solvent, chromatography(silica gel, gradient of 20%-30% ethyl acetate in hexane) of the residueafforded 3.4 g (69%) of (1R,2R)-2-Hydroxy-1-methylpropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate.¹H NMR (400 MHz, CDCl₃): δ 1.08 (d, J=6.4 Hz, 3H), 1.11 (d, J=6.4 Hz,3H), 1.41 (s, 9H), 2.96 (m, 2H), 3.66 (s, br, 1H), 4.34 (m, 1H), 4.75(m, 1H), 4.98 (m, 1H), 5.10 (s, 4H), 6.66 (d, J=8 Hz, 1H), 6.77 (s, 1H),6.82 (d, J=8 Hz, 1H), 7.26-7.41 (m, 10H).

Step B (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate

To a solution of benzoic acid (0.57 g, 4.8 mmol) in anhydrousdichloromethane was added triethylamine (1.7 mL, 12 mmol), and2,4,6-trichlorobenzoyl chloride (0.9 mL, 5.76 mmol) were added. Theresulting mixture was stirred for 30 min and a solution of(1R,2R)-2-hydroxy-1-methylpropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate(2.4 g, 4.4 mmol) in dichloromethane was slowly added to the reactionmixture, followed by the addition of a catalytic amount of4-(dimethylamino)pyridine. The resulting mixture was stirred at roomtemperature for 16 hrs, washed with 10% citric acid, dried over Na₂SO₄,and concentrated. Chromatography (silica gel, 20% ethyl acetate inhexane) of the residue afforded 2.6 g (90%) of(1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate.¹H NMR (400 MHz, CDCl₃): δ 1.26 (d, J=6.4 Hz, 6H), 1.39 (s, 9H), 2.78(m, 1H), 2.96 (m, 1H), 4.51 (m, 1H), 4.89 (d, 1H), 5.10 (s, 4H), 5.15(m, 1H), 6.57 (d, J=8 Hz, 1H), 6.71 (s, 1H), 6.77 (d, J=8 Hz, 1H),7.25-7.43 (m, 12H), 7.52 (t, J=7.6 Hz, 1H), 7.99 (d, J=7.6 Hz, 2H).

Step C (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate

200 mg of 10% Pd—C pre-mixed with 10 mL of methanol was added to asolution of (1R,2R)-1-methyl-2-phenylcarbonyloxypropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate(2.6 g, 3.9 mmol) in 40 mL of tetrahydrofuran under a nitrogenatmosphere. The resulting mixture was stirred under hydrogen at roomtemperature for 2 hrs. After filtration and washing with methanol, thefiltrate was concentrated and chromatography (silica gel, 30% ethylacetate in hexane) of the residue afforded 1.8 g (95%) of(1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate.MS (ESI) m/z 474.31 (M+H)⁺ and 472.18 (M−H)⁻.

Step D (1R,2R)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

(1R,2R)-1-methyl-2-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate(1.8 g, 2.7 mmol) was dissolved in 40 mL of 4M HCl in dioxane. Themixture was stirred at room temperature for 30 min. The dioxane wasevaporated completely under reduced pressure. The resulting a whitesolid was dissolved in acetonitrile (5 mL), and ether added until thesolution became slightly cloudy. The solution was refrigeratedovernight, and the product crystallized. The white crystalline solid wascollected and dried under vacuum to afford 1.0 g (87%) of the titlecompound. ¹H NMR (400 MHz, CD₃OD): δ 1.12 (d, J=6 Hz, 3H), 1.24 (d, J=6Hz, 3H), 2.85 (dd, J=8, 14 Hz, 1H), 3.02 (dd, J=5.2, 14 Hz, 1H), 4.15(t, J=5.6 Hz, 1H), 5.06 (m, 2H), 6.46 (dd, J=2, 8 Hz, 1H), 6.61 (d, J=2Hz, 1H), 6.65 (d, J=8 Hz, 1H), 7.54 (t, J=7.6 Hz, 2H), 7.65 (t, J=7.6Hz, 1H), 7.90 (m, 2H). MS (ESI) m/z 374.11 (M+H)⁺ and 372.08 (M−H)⁻.

Example 17 (1S,2S)-1-Methyl-2-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 16, and substituting(2R,3R)-(−)-2,3-butanoldiol with (2S,3S)-(+)-2,3-butanediol, providedthe title compound (34% over 4 steps) as a white solid. ¹H NMR (400 MHz,CD₃OD): δ 1.30 (d, J=6 Hz, 3H), 1.34 (d, J=6 Hz, 3H), 2.68 (dd, J=8,14.4 Hz, 1H), 2.94 (dd, J=6, 14.4 Hz, 1H), 4.01 (dd, J=5.6, 8 Hz, 1H),5.20 (m, 2H), 6.44 (dd, J=2, 8 Hz, 1H), 6.59 (d, J=2 Hz, 1H), 6.66 (d,J=8 Hz, 1H), 7.46 (t, J=7.6 Hz, 2H), 7.59 (t, J=7.6 Hz, 1H), 7.99 (m,2H). MS (ESI) m/z 374.16 (M+H)⁺ and 372.08 (M−H)⁻.

Example 18 (1R,2R)-1-Methyl-2-(4-fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 16, and substitutingbenzoic acid with 4-fluorobenzoic acid, provided the title compound (42%over 4 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.24 (d,J=6.4 Hz, 3H), 1.32 (d, J=6.4 Hz, 3H), 3.06 (d, J=6.4 Hz, 2H), 4.21 (t,J=6.8 Hz, 1H), 5.19 (m, 2H), 6.57 (dd, J=2, 8 Hz, 1H), 6.71 (d, J=2 Hz,1H), 6.74 (d, J=8 Hz, 1H), 7.24 (t, J=8.8 Hz, 2H), 8.02 (dd, J=5.2, 8.8Hz, 2H). MS (ESI) m/z 392.20 (M+H)⁺ and 390.15 (M−H)⁻.

Example 19 (1S,2S)-1-Methyl-2-(4-fluorophenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 16, substituting benzoicacid with 4-fluorobenzoic acid and (2R,3R)-(−)-2,3-butanediol with(2S,3S)-(+)-2,3-butanediol separately, provided the title compound (47%over 4 steps) as a white solid. ¹H NMR (400 MHz, CD₃OD): δ 1.32 (d, J=6Hz, 3H), 1.36 (d, J=6 Hz, 3H), 2.75 (dd, J=8, 14.4 Hz, 1H), 3.02 (dd,J=5.6, 14.4 Hz, 1H), 4.22 (dd, J=6, 8 Hz, 1H), 5.23 (m, 1H), 6.46 (dd,J=2, 8 Hz, 1H), 6.61 (d, J=2 Hz, 1H), 6.68 (d, J=8 Hz, 1H), 7.19 (t,J=8.4 Hz, 2H), 8.05 (dd, J=5.2, 8.4 Hz, 2H). MS (ESI) m/z 392.15 (M+H)⁺and 390.10 (M−H)⁻.

Example 20 3-(4-Methoxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step A3-Bromopropyl 4-methoxybenzoate

1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC) (3.4g, 17.7 mmol) was slowly added to a solution of 4-methoxybenzoic acid(2.0 g, 13.1 mmol), 3-bromopropan-1-ol (1.1 mL, 12.6 mmol), and4-(dimethylamino)pyridine (100 mg) in 80 mL of anhydrousdichloromethane. The mixture was stirred at room temperature for 16 hrs.The reaction mixture was diluted with dichloromethane and washed with0.5N HCl twice, followed by the addition of saturated NaHCO₃ solutionand brine. The organic layer was dried through MgSO₄ and concentratedunder reduced pressure. Chromatography (silica gel, 1:10 ethylacetate/hexane) of the residue afforded 2.1 g (61%) of 3-Bromopropyl4-methoxybenzoate.

Step B 3-(4-Methoxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

A suspension of 3-bromopropyl 4-methoxybenzoate (2.1 g, 7.7 mmol),(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoicacid (3.43 g, 11.5 mmol), and cesium bicarbonate (2.98 g, 15.4 mmol) in1-methyl-2-pyrrolidinone (40 mL) was stirred at 50° C. for 3 hrs. Thereaction mixture was diluted with ether and washed with water threetimes followed by brine. The organic layer was separated, dried througha MgSO₄ pad and concentrated under reduced pressure. Chromatography(silica gel, 1:1 ethyl acetate/hexane) of the residue provided 3.7 g(98%) of a clear viscous oil. The oil was treated with 4.0M HCl in1,4-dioxane at room temperature for 30 min. The reaction mixture wasconcentrated to dryness under reduced pressure. The resulting viscousoil was purified by prep-HPLC. The HPLC fractions were pooled, treatedwith 20 mL of 0.5N HCl, and dried by lyophilization to yield 1.3 g (41%)of the title compound as a white solid. ¹H NMR (400 MHz, D₂O): δ1.98-2.16 (m, 2H), 2.91 (dd, J=7.4, 15.0 Hz, 1H), 2.97 (dd, J=6.4, 15.2Hz, 1H), 3.79 (s, 3H), 4.20 (t, J=6.8 Hz, 1H), 4.26 (t, J=5.8 Hz, 2H),4.29-4.40 (m, 2H), 6.47 (dd, J=2.2, 8.2 Hz, 1H), 6.60 (d, J=2.0 Hz, 1H),6.72 (d, J=8.0 Hz, 1H), 6.91 (d, J=8.8 Hz, 2H), 7.87 (d, J=8.8 Hz, 2H);MS (ESI) m/z 390.17 (M+H)⁺.

Example 21 3-(2-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step A3-Bromopropyl 2-(phenylmethoxy)benzoate

To a solution of 2-(phenylmethoxy)benzoic acid (1.0 g, 4.4 mmol),3-bromopropan-1-ol (0.35 mL, 4.0 mmol), and 4-(dimethylamino)pyridine(50 mg) in 20 mL of anhydrous dichloromethane,1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC) (1.3g, 6.6 mmol) was slowly added. The resulting mixture was stirred at roomtemperature for 16 hrs. The reaction mixture was diluted withdichloromethane and washed with 0.5N HCl three times followed by theaddition of a saturated NaHCO₃ solution and brine. The organic layer wasseparated, dried through a MgSO₄ pad, and concentrated under reducedpressure. Chromatography (silica gel, 1:9 ethyl acetate/hexane) of theresidue afforded 0.8 g (58%) of 3-Bromopropyl 2-(phenylmethoxy)benzoate.

Step B 3-(2-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

A suspension of 3-bromopropyl 2-(phenylmethoxy)benzoate (0.8 g, 2.3mmol),(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoicacid (1.0 g, 3.4 mmol), and cesium bicarbonate (0.89 g, 4.6 mmol) in1-methyl-2-pyrrolidinone (15 mL) was stirred at 50° C. for 3 hrs. Thereaction mixture was diluted with ether and washed with water twicefollowed by brine. The organic layer was dried through MgSO₄ andconcentrated under reduced pressure. Chromatography (silica gel, 1:1ethyl acetate/hexane) of the residue gave 1.2 g (93%) of a clear viscousoil. To the solution of the oil in THF was added 300 mg of 10% Pd/C. Theair in the flask was removed under vacuum and replaced with 1 atm H₂.The suspension was stirred under H₂ at room temperature overnight. Thereaction mixture was filtered through a Celite pad. The solvent wasremoved under vacuum. The resulting viscous oil was treated with 4.0 MHCl in 1,4-dioxane at room temperature for 30 min. The reaction mixturewas concentrated to dryness under reduced pressure and purified byprep-HPLC. The HPLC fractions were pooled, treated with 10 mL of 0.5NHCl, and dried by lyophilization to yield 545 mg (68%) of the titlecompound as a white solid. ¹H NMR (400 MHz, D₂O): δ 1.86-2.10 (m, 2H),2.91 (dd, J=7.0, 14.6 Hz, 1H), 2.96 (dd, J=6.6, 15.0 Hz, 1H), 4.08-4.20(m, 2H), 4.19 (t, J=6.8 Hz, 1H), 4.26 (t, J=5.8 Hz, 2H), 6.42 (dd,J=2.2, 8.2 Hz, 1H), 6.58 (d, J=2.0 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.78(t, J=7.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.36 (dt, J=1.4, 7.2 Hz, 1H),7.59 (dd, J=1.2, 8.0 Hz, 1H); MS (ESI) m/z 376.08 (M+H)⁺.

Example 22 3-(4-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 21, and substituting2-(phenylmethoxy)benzoic acid with 4-(phenylmethoxy)benzoic acid,provided the title compound as a white solid (41% over two steps). ¹HNMR (400 MHz, D₂O): δ 1.94-2.14 (m, 2H), 2.99 (dd, J=6.4, 14.8 Hz, 1H),2.95 (dd, J=7.2, 14.4 Hz, 1H), 4.12-4.28 (m, 3H), 4.32 (t, J=5.8 Hz,2H), 6.47 (dd, J=2.0, 8.0 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.72 (d,J=8.4 Hz, 1H), 6.83 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H); MS (ESI)m/z 376.08 (M#H)⁺.

Example 23 2-Hydroxy-3-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step AOxiran-2-ylmethyl benzoate

Benzoyl chloride (1.2 mL, 10.0 mmol) was added to a solution of glycidol(0.67 mL, 10.0 mmol) and pyridine (0.81 mL, 10.0 mmol) in anhydrousdichloromethane at 0° C. The reaction mixture was further stirred at 0°C. for 60 min. The reaction mixture was then concentrated to drynessunder reduced pressure, diluted with ethyl acetate, and washed with 10%citric acid twice followed by the addition of a saturated NaHCO₃solution and brine. The organic phase was dried over MgSO₄ andconcentrated to dryness to yield 1.8 g (100%) of Oxiran-2-ylmethylbenzoate.

Step B 2-Hydroxy-3-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate

A solution of oxiran-2-ylmethyl benzoate (3.0 g, 16.8 mmol),(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoicacid (6.0 g, 20.2 mmol), and tetrabutylammonium bromide (542 mg, 1.7mmol) in anhydrous toluene was heated to 90° C. for 18 hrs. The reactionmixture was concentrated to dryness under reduced pressure, diluted withethyl acetate, and washed with water twice followed by the addition of asaturated NaHCO₃ solution and brine. The organic layer was dried throughMgSO₄ and concentrated under reduced pressure. Chromatography (silicagel, 1:1 ethyl acetate/hexane) of the residue afforded 2.05 g (26%) of2-Hydroxy-3-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate.

Step C 2-Hydroxy-3-phenylcarbonyloxypropyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

2-Hydroxy-3-phenylcarbonyloxypropyl(2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate(2.05 g, 4.3 mmol) was treated with 4.0M HCl in 1,4-dioxane at roomtemperature for 30 min. The reaction mixture was concentrated to drynessunder reduced pressure and purified by prep-HPLC. The HPLC fractionswere pooled, treated with 10 mL of 0.5N HCl, and dried by lyophilizationto yield 0.85 g (48%) of the title compound as a white solid. ¹H NMR(400 MHz, D₂O): δ 3.11 (t, J=6.6 Hz, 2H), 4.38-4.44 (m, 6H), 6.60 (dd,J=2.2, 7.8 Hz, 1/2H), 6.61 (dd, J=2.4, 8.0 Hz, 1/2H), 6.70 (d, J=2.0 Hz,1/2H), 6.71 (d, J=2.0 Hz, 1/2H), 6.77 (d, J=8.0 Hz, 1/2H), 6.78 (d,J=8.0 Hz, 1/2H), 7.46-7.52 (m, 2H), 7.60-7.68 (m, 1H), 7.96-8.02 (m,2H); MS (ESI) m/z 376.15 (M+H)⁺.

Example 24 (2R)-2-(2-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step A(2R)-1-(tert-Butyldimethylsiloxy)propan-2-ol

A solution of tert-butyldimethylchlorosilane (9.9 g, 65.7 mmol) indichloromethane was added dropwise to a solution of(R)-(−)-1,2-propanediol (5 g, 65.7 mmol) and imidazole (4.47 g, 65.7mmol) in anhydrous dichloromethane at 0° C. The reaction mixture wasstirred at 0° C. for 30 min before dilution with dichloromethane. Thesolution was washed with water three times followed by the addition ofbrine. The organic layer was separated, dried through a MgSO₄ pad andconcentrated under reduced pressure to afford 12.0 g (96%) of(2R)-1-(tert-Butyldimethylsiloxy)propan-2-ol.

Step B (1R)-1-Methyl-2-(tert-butyldimethylsiloxy)ethyl2-(phenylmethoxy)benzoate

To a solution of 2-(phenylmethoxy)benzoic acid (4.0 g, 17.5 mmol),(2R)-1-(tert-butyldimethylsiloxy)propan-2-ol (2.78 g, 14.6 mmol), and4-(dimethylamino)pyridine (183 mg) in 100 mL of anhydrousdichloromethane, 1-(3-dimethylaminopropyl)3-ethylcarbodiimidehydrochloride (EDAC) (4.2 g, 17.5 mmol) was slowly added. The resultingmixture was stirred at room temperature for 48 hrs. The reaction mixturewas diluted with dichloromethane and washed with 0.5N HCl twice followedby the addition of saturated NaHCO₃ solution and brine. The organiclayer was separated, dried through a MgSO₄ pad, and concentrated underreduced pressure. Chromatography (silica gel, 1:12 ethyl acetate/hexane)of the residue afforded 1.7 g (29%) of(1R)-1-Methyl-2-(tert-butyldimethylsiloxy)ethyl2-(phenylmethoxy)benzoate.

Step C (1R)-2-Hydroxy-isopropyl 2-(Phenylmethoxy)benzoate

Triethylamine trihydrofluoride (1.7 mL, 10.5 mmol) was added slowly to asolution of (1R)-1-methyl-2-(tert-butyldimethylsiloxy)ethyl2-(phenylmethoxy)benzoate (1.7 g, 4.24 mmol) in anhydroustetrahydrofuran. The mixture was stirred at room temperature for 48 hrs.The solvent was removed under reduced pressure. The reaction mixture wasdiluted with dichloromethane and washed with saturated NaHCO₃ solutiontwice followed by the addition of brine. The organic layer was driedthrough MgSO₄ and concentrated under reduced pressure. Chromatography(silica gel, 1:5 ethyl acetate/hexane) of the residue afforded 1.5 g(100%) of (1R)-2-Hydroxy-isopropyl 2-(phenylmethoxy)benzoate.

Step D (2R)-2-[2-(phenylmethyloxy)phenylcarbonyloxy]propyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethyloxy)phenyl]propanoate

1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC) (1.5g, 7.86 mmol) was slowly added to a solution of(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoicacid (2.75 g, 5.76 mmol), (1R)-2-hydroxy-isopropyl2-(phenylmethoxy)benzoate (1.5 g, 5.24 mmol), and4-(dimethylamino)pyridine (64 mg) in 40 mL of anhydrous dichloromethane.The resulting mixture was stirred at room temperature for 16 hrs. Thereaction mixture was diluted with dichloromethane and washed with 0.5NHCl twice followed by the addition of saturated NaHCO₃ solution andbrine. The organic layer was separated, dried through a MgSO₄ pad andconcentrated under reduced pressure. Chromatography (silica gel, 1:3ethyl acetate/hexane) of the residue afforded 3.5 g (90%) of(2R)-2-[2-(phenylmethyloxy)phenylcarbonyloxy]propyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethyloxy)phenyl]propanoate.

Step E (2R)-2-(2-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

1.0 g of 10% Pd/C was added to a solution of(2R)-2-[2-(phenylmethyloxy)phenylcarbonyloxy]propyl(2S)-2-[(1,1-dimethylethyloxy)carbonylamino]-3-[3,4bis(phenylmethyloxy)phenyl]propanoate(3.5 g, 4.69 mmol) in THF. The air in the flask was removed under vacuumand replaced with 1 atm H₂. The suspension was stirred under H₂ at roomtemperature overnight. The reaction mixture was filtered through aCelite pad. The solvent was removed under vacuum. The resulting viscousoil was treated with 4.0M HCl in 1,4-dioxane at room temperature for 30min. The reaction mixture was concentrated to dryness under reducedpressure and purified by prep-HPLC. The HPLC fractions were pooled,treated with 10 mL of 0.5N HCl, and dried by lyophilization to yield 1.2g (62%) of the title compound as a white solid. ¹H NMR (400 MHz, D₂O): δ1.30 (d, J=6.4 Hz, 3H), 2.97 (dd, J=6.6, 14.2 Hz, 1H), 3.02 (dd, J=6.2,14.2 Hz, 1H), 4.27 (dd, J=6.6, 12.2 Hz, 1H), 4.30 (t, J=7.0 Hz, 1H),4.49 (dd, J=2.8, 12.0 Hz, 1H), 5.22 (doublet of pentets, J=2.4, 6.4 Hz,1H), 6.47 (dd, J=2.2, 8.2 Hz, 1H), 6.62 (d, J=2.0 Hz, 1H), 6.63 (d,J=8.4 Hz, 1H), 6.81 (t, J=7.6 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 7.39 (dt,J=1.6, 7.0 Hz, 1H), 7.62 (dd, J=1.4, 7.8 Hz, 1H); MS (ESI) m/z 376.15(M+H)⁺.

Example 25 (2R)-2-(4-Hydroxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 24, and substituting2-(phenylmethoxy)benzoic acid with 4-(phenylmethoxy)benzoic acid,provided the title compound (14% over five steps). ¹H NMR (400 MHz,D₂O): δ 1.26 (d, J=6.4 Hz, 3H), 2.95 (dd, J=7.0, 14.6 Hz, 1H), 3.01 (dd,J=6.6, 14.6 Hz, 1H), 4.24 (dd, J=6.4, 12.0 Hz, 1H), 4.27 (t, J=6.6 Hz,1H), 4.45 (dd, J=3.0, 11.8 Hz, 1H), 5.16 (doublet of pentets, J=2.4, 6.4Hz, 1H), 6.45 (dd, J=2.0, 8.0 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.63 (d,J=8.0 Hz, 1H), 6.78 (d, J=8.8 Hz, 2H), 7.70 (d, J=8.8 Hz, 2H); MS (ESI)m/z 376.15 (M+H)⁺.

Example 26 (2R)-2-(4-Methoxyphenylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

Following the procedure described in Example 24, and substituting2-(phenylmethoxy)benzoic acid with 4-methoxybenzoic acid, provided thetitle compound as a white solid (32% over five steps). ¹H NMR (400 MHz,D₂O): δ 1.26 (d, J=6.8 Hz, 3H), 2.91 (dd, J=7.4, 14.6 Hz, 1H), 2.98 (dd,J=6.2, 14.6 Hz, 1H), 3.64 (s, 3H), 4.22 (dd, J=6.4, 12.0 Hz, 1H), 4.27(t, J=6.8 Hz, 1H), 4.47 (dd, J=2.6, 11.8 Hz, 1H), 5.17 (doublet ofpentets, J=2.8, 6.4 Hz, 1H), 6.41 (dd, J=2.0, 8.4 Hz, 1H), 6.60 (d,J=2.4 Hz, 1H), 6.61 (d, J=8.0 Hz, 11H), 6.69 (d, J=8.8 Hz, 2H), 7.65 (d,J=8.8 Hz, 2H); MS (ESI) m/z 390.32 (M+H)⁺.

Example 27 2-[(2-Hydroxyphenyl)carbonylamino]ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride Step AN-(2-Hydroxyethyl)[2-(phenylmethoxy)phenyl]carboxamide

1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC) (1.3g, 6.57 mmol) was slowly added to a solution of 2-(phenylmethoxy)benzoicacid (1.5 g, 6.57 mmol), 1-hydroxybenzotriazole (HOBt) (0.89 g, 6.57mmol), and ethanolamine (0.40 mL, 6.57 mmol) in 50 mL of anhydrous THFat 0° C. The suspension was stirred and warmed up slowly to roomtemperature over 24 hrs. The reaction mixture was concentrated todryness under reduced pressure and the resulting residue was dilutedwith dichloromethane and washed with 0.5N HCl twice followed by theaddition of a saturated NaHCO₃ solution and brine. The organic layer wasseparated, dried through a MgSO₄ pad and concentrated under reducedpressure to afford 1.8 g (100%) ofN-(2-Hydroxyethyl)[2-(phenylmethoxy)phenyl]carboxamide.

Step B 2-{[2-(Phenylmethoxy)phenyl]carbonylamino}ethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate

To a solution of(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoicacid (3.95 g, 8.27 mmol),N-(2-hydroxyethyl)[2-(phenylmethoxy)phenyl]carboxamide (1.8 g, 6.63mmol), and 4-(dimethylamino)pyridine (84 mg) in 40 mL of anhydrousdichloromethane was added slowly1-(3-dimethylaminopropyl)3-ethylcarbodiimide hydrochloride (EDAC) (2.0g, 10.34 mmol) was slowly added. The resulting mixture was stirred atroom temperature for 16 hrs. The reaction mixture was diluted withdichloromethane and washed with 0.5N HCl twice followed by the additionof brine. The organic layer was separated, dried through MgSO₄ andconcentrated under reduced pressure. Chromatography (silica gel, 1:2then 1:1.5 ethyl acetate/hexane) of the residue afforded 3.7 g (73%) of2-{[2-(Phenylmethoxy)phenyl]carbonylamino}ethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate.

Step C 2-[(2-Hydroxyphenyl)carbonylamino]ethyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride

To a solution of 2-{[2-(phenylmethoxy)phenyl]carbonylamino}ethyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate(3.7 g, 5.06 mmol) in THF was added 1.0 g of 10% Pd/C. The air in theflask was removed under vacuum and replaced with 1 atm H₂. Thesuspension was stirred under H₂ at room temperature overnight. Thereaction mixture was filtered through a Celite pad. The solvent wasremoved under vacuum. The resulting viscous oil was treated with 4.0MHCl in 1,4-dioxane at room temperature for 30 min. The reaction mixturewas concentrated to dryness under reduced pressure and purified byprep-HPLC. The HPLC fractions were pooled, treated with 15 mL of 0.5NHCl, and dried by lyophilization to yield 1.2 g (61%) of the titlecompound as a white solid. ¹H NMR (400 MHz, D₂O): δ 2.86 (dd, J=6.8,14.8 Hz, 1H), 2.91 (dd, J=6.0, 14.8 Hz, 1H), 3.38-3.62 (m, 2H),4.14-4.30 (m, 2H), 4.19 (t, J=6.6 Hz, 1H), 6.34 (dd, J=2.2, 8.2 Hz, 1H),6.49 (d, J=2.0 Hz, 1H), 6.52 (d, J=8.0 Hz, 1H), 6.70 (dd, J=0.8, 8.4 Hz,1H), 6.73 (dt, J=1.2, 7.8 Hz, 1H), 7.18 (ddd, J=1.6, 7.2, 7.4 Hz, 1H),7.42 (dd, J=1.6, 8.0 Hz, 1H); MS (ESI) m/z 361.28 (M+H)⁺.

Example 28 2(R)- and2(S)-(3-Pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoatesStep A 1-Bromoisopropyl nicotinate

Nicotinic acid chloride (2.56 g, 20 mmol) and 30 mg of DMAP were addedto a mixture of 2-bromo-2-propanol (2.8 g, 20 mmol), triethylamine (5.6mL, 20 mmol) in dichloromethane at 0° C. The resulting mixture wasstirred at room temperature overnight. The product was partitionedbetween ethyl acetate and water. The organic phase was separated, driedover MgSO₄, and concentrated to yield 1-Bromoisopropyl nicotinate, whichwas used in the next reaction without further purification.

Step B(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propionicacid cesium salt

Cesium hydrogencarbonate (194 mg, 1 mmol) was added to a solution of(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propionicacid (297 mg, 1 mmol) in 5 mL water and 5 mL acetonitrile. The resultingmixture was stirred at room temperature for 10 minutes, then frozen andlyophilized to yield(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propionicacid cesium salt as a white solid, which was used in the next reactionwithout further purification.

Step C 2(R)- and 2(S)-(3-Pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoates

1-Bromoisopropyl nicotinate (366 mg, 1.5 mmol) was added to a solutionof(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propionicacid cesium salt (432 mg, 1 mmol) in dimethylacetamide at roomtemperature and the mixture stirred at 55° C. for 16 hrs. After removingthe solvent under reduced pressure, the residue was partitioned betweenethyl acetate and water. The organic phase was separated, dried overMgSO₄, and concentrated. The resulting residue was treated with 30%trifluoroacetic acid in dichloromethane at room temperature for 30 min.After removing the solvent, the resulting residue was purified byreverse phase preparative HPLC to afford 180 mg of the title compoundsas a mixture of two diastereoisomers. MS (ESI) m/z 362.22 (M+H)⁺.

Example 29 2(R)- and 2(S)-(4-Pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoates

Following the procedure described in Example 28, and substitutingnicotinic acid chloride with isonicotinic acid chloride, provided thetitle compounds as a mixture of two diastereoisomers. MS (ESI) m/z362.13 (M+H)⁺.

Example 30 2(R)- and 2(S)-(2-Ethoxy-3-pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoates

Following the procedure described in Example 28, and substitutingnicotinic acid chloride with 1′-ethoxynicotinic acid chloride, providedthe title compounds as a mixture of two diastereoisomers. MS (ESI) m/z406.15 (M+H)⁺.

Example 31 2(R)- and 2(S)-(2-Methyl-5-pyridylcarbonyloxy)propyl(2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoates

Following the procedure described in Example 28, and substitutingnicotinic acid chloride with 6′-methylnicotinic acid chloride, providedthe title compounds as a mixture of two diastereoisomers. MS (ESI) m/z376.31 (M+H)⁺.

Example 32 Uptake of Levodopa Prodrugs Following Administration ofLevodopa Prodrugs and Carbidopa in Rats

Sustained release oral dosage forms, which release drug slowly overperiods of 6 to 24 hours, generally release a significant proportion ofthe dose within the colon. Thus, drugs suitable for use in such dosageforms can exhibit good colonic absorption. This experiment was conductedto assess the uptake and resultant blood levels of levodopa, followingintracolonic administration of levodopa prodrugs with coadministrationof carbidopa (intracolonically, intraperitoneally or orally), andthereby determine the suitability of levodopa prodrugs for use in anoral sustained release dosage form. Bioavailability of levodopafollowing coadministration of levodopa prodrugs and carbidopa wascalculated relative to oral coadministration of levodopa and carbidopa.

Step A Administration Protocol

Rats were obtained commercially and were pre-cannulated in the both theascending colon and the jugular vein. Animals were conscious at the timeof the experiment. All animals were fasted overnight and until 4 hourspost-dosing of levodopa prodrug. Carbidopa was administered as asolution in water or citrate buffer either orally, or intraperitoneallyor intracolonically at a dose equivalent to 25 mg of carbidopa per kg.Either at the same time or 1 hour after carbidopa dosing, levodopa HClsalt or levodopa prodrug HCl salt was administered as a solution (inwater) directly into the colon via the cannula at a dose equivalent to75 mg of levodopa per kg. Blood samples (0.3 mL) were obtained from thejugular cannula at intervals over 8 hours and were quenched immediatelyby addition of sodium metabisulfite to prevent oxidation of levodopa.Blood was then further quenched with methanol/perchloric acid to preventhydrolysis of the levodopa prodrug. Blood samples were analyzed asdescribed below.

Step B Sample Preparation for Colonically Absorbed Drug

1. In blank 1.5 mL tubes, 300 μL of methanol/perchloric acid was added.

2. Rat blood (300 μL) was collected at different times into EDTA tubescontaining 75 μL of sodium metabisulfite, and vortexed to mix. A fixedvolume of blood (100 μL) was immediately added into the Eppendorf tubeand vortexed to mix.

3. Ten microliters of an levodopa standard stock solution (0.04, 0.2, 1,5, 25, 100 μg/mL) and 110 μL of the 10% sodium metabisulfate was addedto 80 μL of blank rat blood to make up a final calibration standard(0.004, 0.02, 0.1, 0.5, 2.5, 10 μg/mL). Then 300 μL of 50/50methanol/perchloric acid was added into each tube followed by 20 μL ofp-chlorophenylalanine.

4. Samples were vortexed and centrifuged at 14,000 rpm for 10 min.

5. Supernatant was analyzed by LC/MS/MS.

Step C LC/MS/MS Analysis

An API 4000 LC/MS/MS spectrometer equipped with Agilent 1100 binarypumps and a CTC HTS-PAL autosampler were used in the analysis. A ZorbaxXDB C8 4.6×150 mm column was used during the analysis. The mobile phasewas 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B). Thegradient condition was: 5% B for 0.5 min, then to 98% B in 3 min, thenmaintained at 98% B for 2.5 min. The mobile phase was returned to 2% Bfor 2 min. A TurboIonSpray source was used on the API 4000. The analysiswas done in positive ion mode and the MRM transition for each analytewas optimized using standard solution. 5 μL of the samples wereinjected. Non-compartmental analysis was performed using WinNonlin(v.3.1 Professional Version, Pharsight Corporation, Mountain View,Calif.) on individual animal profiles. Summary statistics on majorparameter estimates was performed for C_(max) (peak observedconcentration following dosing), T_(max) (time to maximum concentrationis the time at which the peak concentration was observed), AUC_((0-t))(area under the serum concentration-time curve from time zero to lastcollection time, estimated using the log-linear trapezoidal method),AUC_((0-∞)), (area under the serum concentration time curve from timezero to infinity, estimated using the log-linear trapezoidal method tothe last collection time with extrapolation to infinity), and t_(1/2,z)(terminal half-life). Maximum concentrations of levodopa in the blood(C_(max) values) and the area under blood concentration versus timecurve (AUC) values after intracolonic dosing of levodopa prodrugs withcarbidopa were significantly higher (>2-fold) than those achieved forcolonic administration of levodopa with carbidopa.

Intracolonic coadministration of levodopa and carbidopa results in verylow relative bioavailability of levodopa (i.e., only 3% of orallycoadministered levodopa and carbidopa). By comparison, coadministrationof the levodopa prodrugs listed below with carbidopa exhibited improvedrelative bioavailability of levodopa by at least 2-fold. The range ofimproved relative bioavailability of levodopa was between 2 and 20 fold.These data demonstrate that certain levodopa prodrugs can be formulatedas compositions suitable for effective sustained oral release and uptakeof levodopa from the colon.

Levodopa prodrugs which, when administered, produced a relativebioavailability of levodopa at least 2-fold greater than thebioavailability of levodopa produced following the administration oflevodopa include:

-   (2R)-2-Phenylcarbonyloxypropyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (2R)-2-(4-Methoxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (2R)-2-(4-Hydroxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (2R)-2-(2-Hydroxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   2-Hydroxy-3-phenylcarbonyloxypropyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   3-(4-Hydroxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   3-(4-Methoxyphenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (1R,2R)-1-Methyl-2-(4-fluorophenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (1S,2S)-1-Methyl-2-phenylcarbonyloxypropyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (1R)-1-Methyl-2-(4-fluorophenylcarbonyloxy)ethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (1S)-1-Methyl-2-phenylcarbonyloxyethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (2S)-2-(4-Fluorophenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (2R)-2-(4-Fluorophenylcarbonyloxy)propyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   (2S)-2-Phenylcarbonyloxypropyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride;-   2-Phenylcarbonyloxyethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride; and-   (1R)-1-Methyl-2-phenylcarbonyloxyethyl    (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate hydrochloride.

1-61. (canceled)
 62. A method of treating a disease in a patient in needof such treatment comprising administering to the patient atherapeutically effective amount of at least one compound of Formula(I):

a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein Q is —X—CO—; X is selected from —O—, and —NH—; n isan integer from 2 to 4; each R¹ and R² is independently selected fromhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, halo, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl; R³ and R⁴ areindependently selected from hydrogen, —C(O)OR⁷, —C(O)R⁷, and—(CR⁸R⁹)OC(O)R¹⁰; R⁵ is selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; and when Q is —X—CO—, R⁵ is further selected fromalkoxy, substituted alkoxy, cycloalkoxy, and substituted cycloalkoxy; R⁷is selected from alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; R⁸ and R⁹ are independently selected from hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R⁸ andR⁹ together with the carbon atom to which R⁸ and R⁹ are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring; and R¹⁰ is selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; with the proviso that the compound of Formula (I) isnot derived from 1,3-dihexadecanoylpropane-1,2,3-triol.
 63. A methodaccording to claim 62, wherein the disease is Parkinson's disease.
 64. Amethod according to claim 62, wherein the disease is selected fromdepression, attention deficit disorder; schizophrenia, manic depression,cognitive impairment disorders, restless legs syndrome, periodic limbmovement disorders, tardive dyskinesia, Huntington's disease, Tourette'ssyndrome, hypertension, addictive disorders, congestive heart failure,and excessive daytime sleepiness.
 65. A method of achieving sustainedtherapeutic or prophylactic blood concentrations of levodopa or levodopaprodrug thereof, in the systemic circulation of a patient comprisingoral administration of at least one compound of Formula (I):

a stereoisomer thereof, an enantiomer thereof, a pharmaceuticallyacceptable salt thereof, a hydrate thereof, or a solvate of any of theforegoing, wherein Q is —X—CO—; X is selected from —O—, and —NH—; n isan integer from 2 to 4; each R¹ and R² is independently selected fromhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, halo, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl; R³ and R⁴ areindependently selected from hydrogen, —C(O)OR⁷, —C(O)R⁷, and—(CR⁸R⁹)OC(O)R¹⁰; R⁵ is selected from hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; and when Q is —X—CO, R⁵ is further selected fromalkoxy, substituted alkoxy, cycloalkoxy, and substituted cycloalkoxy; R⁷is selected from alkyl, substituted alkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; R⁸ and R⁹ are independently selected from hydrogen,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, and substituted heteroarylalkyl, or optionally, R⁸ andR⁹ together with the carbon atom to which R⁸ and R⁹ are attached form acycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring; and R¹⁰ is selected from hydrogen, alkyl,substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substitutedheteroalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, and substitutedheteroarylalkyl; with the proviso that the compound of Formula (I) isnot derived from 1,3-dihexadecanoylpropane-1,2,3-triol.
 66. A methodaccording to claim 65, wherein the therapeutic or prophylactic bloodconcentration is maintained for at least 4 hours following oraladministration of a single dose comprising at least one compound ofFormula (I).
 67. A method according to claim 65, wherein the therapeuticor prophylactic blood concentration is maintained for at least 8 hoursfollowing oral administration of a single dose comprising at least onecompound of Formula (I).
 68. A method according to claim 65, wherein thetherapeutic or prophylactic blood concentration is maintained for atleast 12 hours following oral administration of a single dose comprisingat least one compound of Formula (I).